Switch control for external pacing system

ABSTRACT

Methods are provided for conducting surgical procedures in a patient wherein, during the surgical procedure, autonomous ventricular electrical conductivity and escape beats are reversibly and transiently suppressed to facilitate the surgical procedure. Also provided are compositions which are capable of inducing ventricular asystole in a patient. The compositions may include an AV node blocker. In one embodiment, compositions including an atrioventricular (AV) node blocker and a β-blocker are provided, wherein the β-blocker is present in an amount sufficient to substantially reduce the amount of AV node blocker required to induce ventricular asystole in the patient. The compositions and methods may be used for inducing temporary ventricular asystole in a beating heart, and to facilitate the performance of a variety of surgical techniques, including minimally invasive microsurgical techniques. Methods for performing a surgical procedure on a human patient are provided wherein a composition capable of inducing transient reversible ventricular asystole is administered to the heart, for example by intracoronary injection. The heart then is electrically paced using an electrical pacing system, thereby to maintain the patient&#39;s blood circulation. The electrical pacing then is selectively intermittently stopped to allow ventricular asystole to occur, and the steps of the surgical or therapeutic procedure, such as suturing, are conducted during the time that the electrical pacing is intermittently stopped. The methods and compositions advantageously may be used in a range of different surgical procedures including cardiac, vascular and neurosurgical procedures.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.09/131,075 filed Aug. 7, 1998, which claims the benefit of U.S.Provisional Application Ser. No. 60/055,127, filed Aug. 8, 1997, thedisclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to compositions and methods thatfacilitate the performance of medical and surgical procedures, such ascardiac surgical procedures, including minimally invasive coronarybypass surgery.

BACKGROUND ART

Heart attacks and angina pectoris (chest pain) are caused by occlusionsin the coronary arteries. Atherosclerosis, the major cause of coronaryartery occlusions, is characterized by deposits of fatty substances,cholesterol, calcium and fibrin within the arterial wall. As thecoronary arteries narrow, blood flow is reduced depriving the heart ofmuch needed oxygen. This occurrence is called myocardial ischemia.Severe and prolonged myocardial ischemia produces irreparable damage tothe heart muscle, pronounced cardiac dysfunction, and possibly death.Apart from medical therapy, atherosclerosis is treated with coronaryartery bypass graft surgery (CABG), percutaneous transluminal coronaryangioplasty (PTCA), stents, atherectomy, and transmyocardial laserrevascularization (TMLR).

In patients where PTCA, stents, and atherectomy are unsuitable orunsuccessful, CABG is the procedure of choice. In the conventional CABGoperation, a long vertical incision is made in the chest, the sternum issplit longitudinally and the halves are spread apart to provide accessto the heart. Two large bore tubes, or cannulas, are then inserteddirectly into the right atrium and the aorta in order to establishcardiopulmonary bypass (CPB). The aorta is occluded with an externalclamp placed proximal to the aortic cannula. A third cannula is insertedproximal to the aortic clamp, and is used for the delivery of acardioplegic solution into the coronary arteries. The hyperkalemiccardioplegic solution protects the heart by stopping atrial andventricular contraction, thereby reducing its metabolic demand. When theheart is not beating, blood flow to the rest of the body is provided bymeans of CPB. Cardiopulmonary bypass involves removing deoxygenatedblood through the cannula in the right atrium, infusing the blood withoxygen, and then returning it through the cannula in the aorta to thepatient. With the heart motionless, the surgeon augments blood flow tothe ischemic heart muscle by redirecting blood around the coronaryartery occlusion. Although there are several methods to bypass anocclusion, the most important method involves using the left internalthoracic artery (LITA). The LITA normally originates from the leftsubclavian artery and courses along the anterior chest wall just lateralof the sternum. For this operation, the LITA is mobilized from the chestwall and, with its proximal origin left intact, the distal end isdivided and sewn to the coronary artery beyond the site of occlusion(most commonly the left anterior descending coronary artery). After theLITA anastomosis is completed and any further arterial or vein graftsare completed, CPB is weaned as the heart resumes its normal rhythm. Thecannulae are removed, temporary pacing wires are sewn to the heart, andplastic tubes are passed through the chest wall and positioned near theheart to drain any residual fluid collection. The two halves of thesternum are approximated using steel wire.

Because the traditional method of performing CABG involves significantoperative trauma and morbidity to the patient, attention has beendirected to developing less invasive surgical techniques that avoidsplitting the sternum. The new techniques are performed with or withoutCPB through smaller incisions placed between the ribs. One method,called port-access, utilizes groin cannulation to establish CPB, whileanother, called minimally invasive direct coronary artery bypass orMIDCAB, is performed on the beating heart and therefore does not requireCPB. Insofar as these techniques succeed in achieving less operativetrauma compared to conventional CABG, postoperative pain is improved,the length of hospitalization is shortened, and the return to normalactivity is hastened. The port-access approach avoids the sternalsplitting incision by employing femoral venoarterial CPB and anintraaortic (endoaortic) balloon catheter that functions as an aorticclamp by means of an expandable balloon at its distal end (Daniel S.Schwartz et al. "Minimally Invasive Cardiopulmonary Bypass WithCardioplegic Arrest: A Closed Chest Technique With Equivalent MyocardialProtection." Journal of Thoracic & Cardiovascular Surgery 1996;111:556-566. John H. Stevens et al. "Port-Access Coronary Artery BypassGrafting: A Proposed Method." Journal of Thoracic & CardiovascularSurgery 1996; 111:567-573. John H. Stevens et al. "Port-Access CoronaryArtery Bypass With Cardioplegic Arrest: Acute and Chronic CanineStudies." Annals of Thoracic Surgery 1996; 62:435-441). This catheteralso includes a separate lumen for the delivery of cardioplegic solutionand venting of the aortic root. Alternatively, a different catheter maybe placed percutaneously into the internal jugular vein and positionedin the coronary sinus for delivery of retrograde cardioplegic solution.Coronary bypass grafting is performed through a separate limited leftanterior thoracotomy incision with dissection of the LITA andanastomosis to the atherosclerotic coronary artery under direct vision.Other bypass grafts to coronary arteries can be accomplished usingradial artery sewn to the LITA. A description of port-access proceduresis found in U.S. Pat. No. 5,452,733, the complete disclosure of which isincorporated herein by reference. Thus, the port-access approach focuseson avoiding the sternal splitting incision while maintaining amotionless heart to facilitate a precise coronary anastomosis as theprimary means to reduce operative trauma and morbidity. Compellingevidence to support this contention, however, is scarce. Furthermore, noevidence exists regarding the effectiveness of the coronary anastomosisperformed through the limited incision, nor the safety of theintraaortic balloon clamp and the vascular sequelae of groincannulation. Finally, the port-access approach does not avoid thedamaging effects of cardiopulmonary bypass, which include: 1) a systemicinflammatory response; 2) interstitial pulmonary edema; 3)neuropsychological impairment; 4) acute renal insufficiency; and 5)nonmechanical microvascular hemorrhage.

The MIDCAB approach also avoids the sternal splitting incision, favoringinstead a limited left anterior thoracotomy incision (Tea E. Acuff etal. "Minimally Invasive Coronary Artery Bypass Grafting." Annals ofThoracic Surgery 1996; 61:135-7. Federico J. Benetti and CarlosBallester, "Use Of Thoracoscopy And A Minimal Thoracotomy, InMammary-Coronary Bypass To Left Anterior Descending Artery, WithoutExtracorporeal Circulation." Journal of Cardiovascular Surgery 1995;36:159-61. Federico J. Benetti et al. "Video Assisted Coronary BypassSurgery." Journal of Cardiac Surgery 1995; 10:620-625). Similarly,dissection of the LITA and anastomosis to the coronary artery are thenperformed under direct vision. The principal difference between theMIDCAB and port-access techniques, however, involves the utilization ofcardioplegic solution and CPB (Denton A. Cooley, "Limited AccessMyocardial Revascularization" Texas Heart Institute Journal 1996;23:81-84; and Antonio M. Calafiore et al., "Left Anterior DescendingCoronary Artery Grafting via Left Anterior Small Thoracotomy withoutCardiopulmonary Bypass," Annals of Thoracic Surgery 1996; 61:1658-65).Because MIDCAB is performed on the beating heart, cardioplegic solution,aortic cross-clamping and CPB are not required. This approach thereforefocuses on the avoidance of cardiopulmonary bypass, aorticcross-clamping and the sternal splitting incision as the primary meansto reduce operative trauma and morbidity after conventional CABG.

The potential advantages of MIDCAB compared to conventional CABGinclude: 1) the avoidance of CPB and aortic cross-clamping; 2) fewerembolic strokes; 3) less blood loss, hence a decreased transfusionrequirement; 4) fewer perioperative supraventricular arrhythmias; 5)earlier separation from mechanical ventilatory support; 6) decreased oreliminated intensive care unit stay; 7) shorter length ofhospitalization; 8) reduced total convalescence with earlier return topreoperative activity level; and 9) lower overall cost. Despite thesepotential benefits, however, the durability of the LITA to coronaryartery anastomosis is uncertain. At the recent American HeartAssociation 69th Annual Scientific Session, the Mayo Clinic groupreported on 15 patients undergoing MIDCAB. Of these 15 patients, threeor 20% required reoperation to revise the anastomosis during the samehospitalization (Hartzell V. Schaff et al., "Minimal Thoracotomy ForCoronary Artery Bypass: Value Of Immediate Postprocedure GraftAngiography," Abstract presented at the American Heart Association, 69thScientific Sessions, Nov. 10-13, 1996, Atlanta, Ga.). Of greatersignificance, however, was a report from Loma Linda University MedicalCenter that demonstrated a seven-year LITA to left anterior descendingcoronary artery patency rate of 42% in a subset of patients whounderwent beating heart surgery and presented with recurrent angina. Incontrast, the patency rate in an age-, sex- and disease severity-matchedcontrol group was 92% (Steven R. Gundry et al., "Coronary Artery Bypasswith and Without the Heart-Lung Machine: A Case Matched 6-yearFollow-up," Abstract presented at the American Heart Association, 69thScientific Sessions, Nov. 10-13, 1996, Atlanta, Ga.). Finally, becausethe MIDCAB approach is restricted mostly to patients with isolateddisease of the left anterior descending coronary artery, the vastmajority of patients with atherosclerotic heart disease are notappropriate candidates. Thus, despite the potential benefits of MIDCAB,its safety, efficacy, and applicability remain uncertain.

There are major obstacles to precise coronary anastomosis during MIDCAB.The constant translational motion of the heart and bleeding from theopening in the coronary artery hinder precise suture placement in theoften tiny coronary vessel. Although bleeding can be reduced by usingproximal and distal coronary occluders, by excluding diagonal and septalbranches near the arterial opening when possible, and by continuoussaline irrigation or humidified carbon dioxide insufflation, theincessant motion of the beating heart remains the Achilles' heel ofminimally invasive coronary artery bypass.

In summary, although port-access and minimally invasive direct coronaryartery bypass techniques avoid the operative trauma and morbidityassociated with the sternal splitting incision, both have seriousdisadvantages. The port-access approach is encumbered by the morbidityof cardiopulmonary bypass and aortic cross-clamping and the cost of theapparatus. Furthermore, the safety of the intraaortic balloon clamp andthe vascular sequelae of groin cannulation are unresolved issues. TheMIDCAB approach is imperiled by the constant motion of the beating heartwhich precludes a precise coronary anastomosis. Reports of poor graftpatency rates and the need for early reoperation in a significantproportion of patients after MIDCAB attests to the technical difficultyof the procedure.

Conventional CABG requires arrest of the heart through the use ofcardioplegic agents, aortic cross-clamping and cardiopulmonary bypass.These cardioplegic agents stop the beating heart to thereby allowprecise suture placement and other surgical procedures. A mixture ofmagnesium sulfate, potassium citrate, and neostigmine has been used toinduce cardioplegia during cardiopulmonary bypass. Sealy et al."Potassium, Magnesium, And Neostigmine For Controlled Cardioplegia: AReport Of Its Use In 34 Patients," Journal of Thoracic Surgery 1959,37:655-59. Although both magnesium and potassium remain integralcomponents of modern cardioplegic solutions, neostigmine was ultimatelyeliminated. Potassium citrate is currently the most commonly usedcardioplegic agent. Potassium impedes excitation-contraction coupling,however, making it impossible to pace the heart by electricalstimulation and necessitating the use of a cardiopulmonary bypass systemto sustain the patient. Other chemical agents that have been used inhuman cardiac operations to slow the rate of ventricular contractioninclude acetylcholine, neostigmine, adenosine, lignocaine, and esmolol.Another agent, carbachol or carbamyl choline, has been used to inducecardiac arrest in experimental animals. Broadley and Rothaul, PflugersArch., 391:147-153 (1981).

Acetylcholine has been used as a cardioplegic agent duringcardiopulmonary bypass. Lam et al., "Induced Cardiac Arrest InIntracardiac Procedures, An Experimental Study," Journal of ThoracicSurgery 1955; 30:620-25; Lam et al., "Clinical Experiences With InducedCardiac Arrest During Intracardiac Surgical Procedures," Annals ofSurgery 1957; 146:439-49; Lam et al., "Induced Cardiac Arrest(Cardioplegia) In Open Heart Procedures," Surgery 1958; 43:7-13; and Lamet al., "Acetylcholine-induced Asystole. An adjunct In Open HeartOperations With Extracorporeal Circulation," in ExtracorporealCirculation 1958, pp. 451-48; Lillehei et al., "The Direct VisionCorrection Of Calcific Aortic Stenosis By Means Of A Pump Oxygenator AndRetrograde Coronary Sinus Perfusion," Disease Of The Chest, 1956,30:123-132; Lillehei et al., "Clinical Experience With RetrogradePerfusion Of The Coronary Sinus For Direct Vision Aortic Valve SurgeryWith Observations Upon Use of Elective Asystole Or Temporary CoronaryIschemia," in Extracorporeal Circulation, 1958, pp. 466-85; Lillehei etal., "The Surgical Treatment Of Stenotic Or Regurgitant Lesions Of TheMitral And Aortic Valves By Direct Vision Utilizing A Pump Oxygenator,"Journal of Thoracic & Cardiovascular Surgery, 1958; 35:154-91. Conrad R.Lam, et al. Annals of Surgery 1957; 146:439-49. Intravenous adenosinehas been used to facilitate MIDCAB. M. Clive Robinson, FirstInternational Live Teleconference. Least-Invasive Coronary Surgery, TheJohn Radcliffe Hospital, Oxford, England, Mar. 21 and 22, 1996.

Ventricular asystole has been achieved by direct injection of lignocaineinto the interventricular septum. Khanna and Cullen, "Coronary ArterySurgery With Induced Temporary Asystole And Intermittent VentricularPacing: An Experimental Study," Cardiovascular Surgery 1996;4(2):231-236. Epicardial pacing wires were placed, and ventricularpacing was employed to maintain an adequate cardiac output. Esmolol hasbeen used as a cardioplegic agent during cardiopulmonary bypass.Mauricio Ede et al., "Beyond Hyperkalemia: Beta-Blocker-Induced CardiacArrest For Normothermic Cardiac Operations," Annals of Thoracic Surgery,1997; 63:721-727.

In summary, there is a need for a surgical approach that avoids therisks and costs of cardiopulmonary bypass while preserving the benefitsof a motionless operative field to achieve a precise coronaryanastomosis. There is a further need for methods and compositions thatenable predictable, controllable, transient arrest of the heart, whichstop or slow the beating heart with acceptable half-life and quick onsetof effect. There is a need for compositions and methods for transientarrest of the heart which can be used in a variety of surgicalprocedures conducted on the heart, vascular system, brain, or othermajor organs, where pulsatile flow, movement associated with arterialpulsations, or bleeding is undesirable during the procedure.

SUMMARY OF THE INVENTION

Methods, compositions and apparatus are provided which are useful formedical and surgical therapeutic applications. The methods andcompositions are useful for cardiac surgery and other procedures, suchas neurosurgery and vascular surgery, which require precise control ofcardiac contraction. Other applications include non-invasive proceduressuch as percutaneous aortic aneurysm graft placement, and invasiveprocedures such as brain surgery. Using the methods and compositionsdisclosed herein for conducting a surgical procedure, such as a coronarybypass, a substantially motionless operative field is provided.

In one aspect, there is provided a method of inducing reversibleventricular asystole in a beating heart in a human patient, the methodcomprising administering a compound and a β-blocker to the heart of thepatient in an amount effective to induce ventricular asystole, whilemaintaining the ability of the heart to be electrically paced, whereinthe β-blocker is administered in amount sufficient to substantiallyreduce the amount of compound required to induce ventricular asystole.In one embodiment, the compound may be an atrioventricular (AV) nodeblocker. The β-blocker may be administered in an amount sufficient toreduce the amount of AV node blocker, which is required to induceventricular asystole, to, for example, about 50% or less by weight ofthe amount of AV node blocker alone required to induce ventricularasystole. The compound may be a cholinergic receptor agonist, such ascarbachol. The cholinergic receptor agonist, such as carbachol, may beadministered in an amount, for example, of about 0.1 to 4.8 μg/kg bodyweight/min. The β-blocker, may be, for example, propranolol. Thepropranolol may be administered, for example, in an amount of about 0.01to 0.07 mg/kg body weight. In one embodiment, the β-blocker ispropranolol and the AV node blocker is carbachol, and the propranolol isadministered prior to or during administration of the carbachol. Thepropranolol and the carbachol may be administered, for example, to thecoronary artery of the patient.

In another embodiment, there is provided a method of inducing reversibleventricular asystole in a beating heart in a human patient, the methodcomprising administering a cholinergic receptor agonist and a β-blockerto the heart of the patient in an amount effective to induce ventricularasystole, wherein the amount administered of the cholinergic receptoragonist alone or the β-blocker alone is not sufficient to induceventricular asystole.

In another embodiment, there is provided a method of conducting asurgical procedure on a human patient comprising: administering aβ-blocker and an AV node blocker to the heart of a human patient toinduce reversible ventricular asystole while maintaining the ability ofthe heart to be electrically paced; electrically pacing the heart withan electrical pacing system; selectively intermittently stopping theelectrical pacing to allow ventricular asystole; and conducting thesurgical procedure during the time that the electrical pacing isintermittently stopped. In one embodiment, the β-blocker is administeredprior to the AV node blocker. The AV node blocker may be a cholinergicagent, such as carbachol. The β-blocker may be administered in an amountsufficient to substantially reduce the amount of AV node blockerrequired to induce ventricular asystole. The surgical procedure may be,for example, a cardiac surgical procedure. In one embodiment, theelectrical pacing is selectively intermittently interrupted by a surgeonconducting the surgical procedure by selectively manipulating a controlthat is functionally coupled to the electrical pacing system. Theβ-blocker and the cholinergic agent may be administered, for example,sequentially or simultaneously, and may be administered, for example, tothe right or left coronary artery, left ventricle, the aorta, the rightventricle, the pulmonary artery, the pulmonary vein, or the coronarysinus. The cholinergic receptor agonist, such as carbachol, may beadministered, for example, in an amount of about 0.1 to 4.8 μg/kg bodyweight/min. The β-blocker, may be, for example, propranolol, which maybe administered, for example, in an amount of about 0.01 to 0.07 mg/kgbody weight. In one embodiment, the β-blocker is propranolol and the AVnode blocker is carbachol, and the propranolol is administered prior toor during administration of the carbachol.

In one embodiment, the propranolol is administered by a single bolusinjection in the right or left coronary artery, prior to theadministration of carbachol, and the carbachol is administered by asingle bolus injection followed by continuous infusion into the right orleft coronary artery to maintain the ventricular asystole. Surgicalprocedures that may be conducted include minimally invasive coronarybypass procedures, neurological procedures and endovascular procedures.Other surgical procedures include treatment of injuries to the liver,spleen, heart, lungs, and major blood vessels, as well aselectrophysiologic procedures and cardiac surgery with or withoutcardiopulmonary bypass.

In another embodiment, there is provided a method of inducing reversibleventricular asystole in a human patient comprising administeringcarbachol to the heart of the patient. The carbachol may beadministered, for example, to the coronary sinus, or may be administeredintraventricularly, or to the aortic root or coronary artery of thepatient. Optionally, propranolol also may be administered to the heartof the patient. The propranolol may be administered, for example, priorto or during the administration of the carbachol.

In a further embodiment, there is provided a method of inducingreversible ventricular asystole in the heart of a human patientcomprising administering carbachol to the patient at a dosage of about 1to 15 mg, for example, about 1 to 12 mg. In another embodiment, there isprovided a method of inducing reversible ventricular asystole in theheart of a human patient, the method comprising administering carbacholto the patient at a rate of 0.1 to 4.8 μg/kg body weight/min.

In another embodiment, there is provided a method of inducing reversibleventricular asystole in the heart of a human patient, the methodcomprising: administering an initial intracoronary bolus of carbachol ofabout 0.1 to 10 μg/kg body weight of the patient; and administering acontinuous intracoronary infusion of carbachol at a rate of about0.1-4.8 μg/kg body weight/min. The initial intracoronary bolus ofcarbachol is administered, for example, over about 1-5 minutes. Theintracoronary infusion of carbachol is administered, for example, over atime period of about 5 to 120 minutes. The initial intracoronary bolusmay comprise, for example about 0.1 to 5 μg carbachol/kg body weight,and may be provided in a suitable pharmaceutically acceptable carrier.

In a further embodiment, there is provided a method of inducingreversible ventricular asystole in a human patient comprising:administering an intracoronary bolus injection of about 0.01 to 0.5 mgof carbachol over about 0.5 to 3 minutes; and administering anintracoronary infusion of carbachol at a rate of about 0.01 to 0.3mg/min over about 30 to 90 minutes.

In a further embodiment, there is provided a method of inducingreversible ventricular asystole of a heart of a human patient whilemaintaining the ability of the heart to be electrically pacedcomprising: administering at least a first compound to the heart of thepatient which is capable of inducing third-degree AV block of the heart;and administering at least a second compound to the heart of the patientwhich alone or in combination with the first compound is capable ofsubstantially suppressing ectopic ventricular beats in the heart whilemaintaining the ability of the heart to be electrically paced.

In another embodiment there is provided a method of inducing reversibleventricular asystole in the heart of a patient, while maintaining theability of the heart to be electrically paced comprising: administeringan AV-node blocker and a compound to the heart of the patient in anamount effective to induce ventricular asystole, while maintaining theability of the heart to be electrically paced, wherein the compound isadministered in an amount sufficient to reduce the amount of AV-nodeblocker required to induce ventricular asystole.

In a further embodiment, a method of performing a surgical procedure ona human patient is provided, the method comprising: administering aneffective amount of a composition capable of inducing reversibleventricular asystole to the patient, while maintaining the ability ofthe heart to be electrically paced; electrically pacing the heart withan electrical pacing system, thereby to maintain the patient's bloodcirculation; selectively intermittently stopping the electrical pacingto allow ventricular asystole; and conducting the surgical procedureduring the time that the electrical pacing is intermittently stopped.The composition capable of inducing ventricular asystole may comprise,in one embodiment, an atrioventricular (AV) node blocker. Thecomposition may further comprise a β-blocker, wherein the β-blocker ispresent in an amount sufficient to substantially reduce the amount of AVnode blocker required to induce ventricular asystole. In anotherembodiment, the composition may comprise a cholinergic agent and aβ-blocker, wherein the amount by weight administered of either thecholinergic agent alone or the β-blocker alone is not sufficient toinduce complete heart block and suppression of ventricular escape beats,but in combination, due to a synergistic effect, is effective to induceventricular asystole.

According to another aspect of the invention, a cardiac surgicalprocedure is conducted by inducing reversible ventricular asystole inthe heart of a human patient without cardiopulmonary bypass, and/orwithout aortic cross-clamping.

According to another aspect, a composition is provided that is capableof inducing reversible ventricular asystole in a patient, whilemaintaining the ability of the heart to be electrically paced. Thecomposition may include an atrioventricular (AV) node blocker. In oneembodiment, the composition may include a compound capable of inducingreversible ventricular asystole in a patient and a β-blocker in anamount sufficient to substantially reduce the amount of the compoundrequired to induce ventricular asystole in the patient. The compositionmay include, for example, an atrioventricular (AV) node blocker, such ascarbachol and a β-blocker, such as propranolol. The β-blocker isprovided in one embodiment in an amount sufficient to substantiallyreduce the amount of AV node blocker required to induce ventricularasystole. For example, the AV node blocker may be present in thecomposition in an amount which is 50% or less by weight, or optionallyabout 1 to 20% by weight of the amount of AV node blocker alone requiredto induce ventricular asystole. The composition may comprise, forexample carbachol in a pharmaceutically acceptable solution at a dosageamount of about 1 to 20 mg. The composition may include propranolol in apharmaceutically acceptable carrier in a dosage form for administrationto a patient in an amount of about 0.01 to 0.07 mg/kg body weight of thepatient. In one embodiment, the composition may comprise propranololpresent in a pharmaceutically acceptable solution at a dosage amount ofabout 1 to 10 mg. Methods are provided for administering an effectiveamount of the compositions to a patient to induce reversible ventricularasystole during a surgical procedure.

In another embodiment, a composition is provided which is capable ofinducing ventricular asystole in a patient, while maintaining theability of the heart to be electrically paced, comprising a cholinergicreceptor agonist and a β-blocker. In one embodiment, the amount ofeither the cholinergic receptor agonist alone or the β-blocker alone inthe composition is not sufficient to induce ventricular asystole in thepatient.

In another embodiment, a sterile dosage form of carbachol is provided,which may be provided in form suitable for use in a surgical procedure.The dosage form of carbachol may be in a pharmaceutically acceptableform for parenteral administration, for example to the cardiovascularsystem, or directly to the heart, such as by intracoronary infusion. Thecarbachol may be provided in a variety of pharmaceutically acceptablecarriers. In one embodiment, a sterile dosage form of carbachol isprovided comprising about 1-20 mg of carbachol in a pharmaceuticallyacceptable carrier. Carriers include aqueous solutions including saline,aqueous solutions including dextrose, water and buffered aqueoussolutions.

In yet another embodiment, the invention provides the use of a β-blockerin the manufacture of a medicament for use in conjunction with acompound capable of inducing reversible ventricular asystole in theheart of a patient, for use in a method of inducing transient reversibleventricular asystole in the heart of a patient, while maintaining theability of the heart be electrically paced, the amount of β-blockerbeing sufficient to reduce substantially the amount of the compoundrequired to induce ventricular asystole.

There is further provided the use of a compound capable of inducingreversible ventricular asystole in the manufacture of a medicament foruse in conjunction with a β-blocker for use in a method of inducingtransient reversible ventricular asystole in the heart of a patient,while maintaining the ability of the heart be electrically paced, theamount of β-blocker being sufficient to reduce substantially the amountof the compound required to induce ventricular asystole.

In another embodiment, there is provided the use of a β-blocker in themanufacture of a medicament for use in conjunction with a cholinergicreceptor agonist, for use in a method of inducing transient reversibleventricular asystole in the heart of a patient, while maintaining theability of the heart to be electrically paced, the amount of thecholinergic receptor agonist administered alone or the β-blockeradministered alone not being sufficient to induce ventricular asystolein the heart of the patient.

In another aspect, there is provided the use of a cholinergic receptoragonist in the manufacture of a medicament for use in conjunction with aβ-blocker, for use in a method of inducing transient reversibleventricular asystole in the heart of a patient, while maintaining theability of the heart to be electrically paced, the amount of cholinergicreceptor agonist administered alone or the β-blocker administered alonenot being sufficient to induce ventricular asystole in the heart of thepatient.

According to another aspect of the invention, a patient may be preparedfor coronary artery bypass by placing at least a portion of a deliverydevice in a coronary vessel of the patient's heart and delivering acardioplegic agent to the AV node of the patient via the coronary vesselwith the device, which may be a catheter, for example. In oneembodiment, the device is placed in the right coronary artery of theheart of the patient. In another embodiment, it is placed in the leftcoronary artery of the heart of the patient. The device may include anoutlet and the outlet placed in the right coronary artery of the heartof the patient and immediately proximal to the AV node artery. Inanother embodiment, the device outlet may be placed in the AV nodeartery. In further embodiments, the device may be placed in the middlecardiac vein of the heart of the patient or in an ostium of a right orleft coronary artery of the heart of the patient. In another embodiment,the device may be introduced through the femoral artery. The device alsomay be introduced through an incision in the aorta of the patient.

According to another aspect of the invention, a kit is providedcomprising one or more agents capable of inducing ventricular asystole.For example, the kit may include separate containers of an AV nodeblocker and a β-blocker. In one embodiment, the kit is provided with afirst container comprising a dosage amount of a cholinergic receptoragonist and a second container comprising a dosage amount of aβ-blocker. Dosage amounts of cholinergic receptor agonist and β-blockermay be included that are suitable for simultaneous, separate orsequential use in a surgical procedure for inducing transient reversibleventricular asystole in a patient. In one embodiment, the cholinergicreceptor agonist is carbachol and the β-blocker is propranolol. Thecarbachol and/or propranolol may be in a pharmaceutically acceptablecarrier. According to one embodiment, the first container contains about1 to 20 mg of carbachol, and the second container contains about 1 to 10mg of propranolol. Other possible components of the kit include pacingelectrodes, drug delivery devices and catheters. The electrodes may be,for example, epicardial or endocardial pacing electrodes. Othercomponents of the kit can include pacing catheters and devices, andcoronary perfusion catheters and devices, catheter introducers, a pumpsystem and/or tubes, or other surgical devices. The drug delivery devicemay be in various forms including a catheter, such as a drug deliverycatheter or guide catheter, a cannula or a syringe and needle assembly.The drug delivery catheter may include an expandable member, and a shafthaving a distal portion, wherein the expandable member is disposed alongthe distal portion. The expandable member may be a low-pressure balloon.The kit may be in packaged combination, such as in a pouch, bag or thelike. The kit may further include instructions for the use of componentsof the kit in a surgical procedure, such as instructions for use ofcompounds to induce transient reversible ventricular asystole in theheart of a patient undergoing a surgical procedure.

According to another aspect of the invention, a pacing system isprovided comprising an extracorporeal pacer for delivering pacingsignals to a human heart, a switch coupled to the pacer, and a switchactuator arranged remote from the pacer. The remote actuator may enhanceprocedure control when used, for example, during a surgical procedure.The pacing system may include pacing leads coupled to the switch andadapted for coupling to the heart of the patient. The switch may beremote from the pacer. The actuator may be remote from the switch.Further, the actuator may take various forms. For example, in oneembodiment, the actuator may comprise a foot pedal and in another, itmay comprise a needle holder. An actuator override circuit also may beprovided as well as indicators indicating various states of pacing.

The above is a brief description of some deficiencies in the prior artand advantages of the present invention. Other features, advantages andembodiments of the invention will be apparent to those skilled in theart from the following description, accompanying drawings and appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 diagramatically shows a pacing system in accordance with theprinciples of the invention;

FIGS. 1A and 1B are circuit diagrams of a control switch and an actuatorused in the pacing system of FIG. 1;

FIG. 1C is a schematic representation of a control box according to thepresent invention;

FIG. 1D diagrammatically shows one outlet lead arrangement coupled tothe heart of a patient;

FIG. 1E diagrammatically shows another outlet lead arrangement coupledto the heart of a patient;

FIG. 2 illustrates a drug delivery catheter prior to insertion into thecoronary sinus in accordance with the invention;

FIG. 2A is a sectional view of the catheter of FIG. 2 taken along line2A--2A;

FIG. 3 illustrates placement of the distal end portion of the catheterof FIG. 2 in the coronary sinus;

FIG. 3A is a sectional view of the distal portion of the catheter ofFIG. 3;

FIG. 4 illustrates another coronary sinus catheter configuration;

FIG. 5 depicts a drug delivery catheter positioned for intra-aortic drugdelivery in accordance with the present invention;

FIG. 6 illustrates a drug delivery catheter positioned for drug deliverylocal to the AV node branch in accordance with the present invention;

FIG. 7 illustrates another embodiment of the catheter of FIG. 6 showinga curved distal end portion for directing fluid toward the AV node; and

FIG. 8 depicts the catheter of FIG. 7 with its bent distal end portiondirected toward the AV node branch.

DETAILED DESCRIPTION

Compositions and methods are provided which are useful for medical andsurgical therapeutic applications. The compositions and methods areuseful for cardiac surgery and other procedures such as neurosurgery andvascular surgery which require precise control of cardiac contraction.In one embodiment, the compositions and methods are useful for coronaryartery bypass procedures, with or without cardiopulmonary bypass. Usingthe methods and compositions for conducting a coronary artery bypassdisclosed herein, a motionless operative field is provided.

The methods and compositions of the invention are useful for anyprocedure which requires controlled temporary complete heart block andsuppression of ventricular escape beats. Examples of such proceduresinclude coronary bypass surgery (with full or partial sternotomy orthoracotomy), transmyocardial laser revascularization, tachyarrhythmiaoperations such as electrophysiology lab procedures (diagnostic andtherapeutic ablation of arrhythmias), imaging procedures of the heartand great vessels such as CAT scan or MRI procedures, percutaneoustransluminal coronary angioplasty, placement of stents such as coronaryor aortic stents, operations where uncontrollable hemorrhage is presentor anticipated or control of significant hemorrhage is required duringthe surgical procedure (for example, treatment of injuries to the liver,spleen, heart, lungs, or major blood vessels, including iatrogenic andtraumatic injuries to such organs or structures), other proceduresincluding percutaneous aortic aneurysm graft placement, andneurosurgical procedures, such as aneurysm repair. The methods andcompositions are useful for any surgical procedure or intervention onthe heart, vascular system, brain, or other major organs, wherepulsatile flow, movement associated with arterial pulsations, orbleeding prevents successful completion of the operative procedure.

The compositions and methods can be used to induce ventricular asystolein a patient, for example, prior to a surgical procedure. The term"ventricular asystole" as used herein refers to a state whereinautonomous electrical conduction and escape rhythms in the ventricle aresuppressed. Preferably, a state of the heart i induced wherein the heartbeats less than about 25 beats per minute, for example, less than about12 beats per minute. The induced ventricular asystole is reversible andafter reversal, the heart functions are restored, and the heart iscapable of continuing autonomous function. Preferred arepharmaceutically acceptable compositions which are capable of inducingtransient reversible ventricular asystole reliably and predictably.

The compositions capable of suppressing autonomous ventrical electricalconduction and escape rhythms may in one embodiment comprise anatrioventricular (AV) node blocker. As used herein, the term "AV nodeblocker" refers to a compound capable of reversibly suppressingautonomous electrical conduction at the AV node, while still allowingthe heart to be electrically paced to maintain cardiac output.Preferably, the AV node blocker, or composition comprising the AV nodeblocker, reduces or blocks ventricular escape beats and cardiac impulsetransmission at the AV node of the heart, while the effect ondepolarization of the pacemaker cells of the heart is minimal ornon-existent. The AV node blocker preferably induces third degree, orcomplete AV block, or significantly slows AV conduction to the pointwhere the ventricular beat is less than about 25 beats per minute, forexample less than about 12 beats per minute. The AV node blocker, orcomposition comprising the AV node blocker, preferably inducesreversible ventricular asystole, and renders the heart totally pacemakerdependent for a limited period of time, such that a pacemaker may beused to maintain pacing and to intermittently stop pacing during asurgical step. After the surgical procedure is completed, for example,less than about 2 hours, the heart then can be returned to its normalintrinsic rhythm.

Exemplary AV node blockers include calcium channel blockers, adenosineA1 receptor agonists, adenosine deaminase inhibitors, cholinesteraseinhibitors, monoamine oxidase inhibitors, serotoninergic agonists,antiarrythmics, cardiac glycosides, local anesthetics and combinationsthereof. Examples of AV node blockers include adenosine, digoxin,digitalis, procaine, lidocaine, procainamide, quinidine, verapamil,chloroquine, amiodarone, ethmozine, propafenone, flecainide, encainide,pilocarpine, diltiazem, dipyridamole, ibutilide, zapranest, sotalol andmetoclopromide and combinations thereof. AV node blocking also can beachieved by other methods including direct electrical stimulation, vagalnerve stimulation, stimulation with ultrasonic energy, and temporarycooling of the AV node using a cryonic agent. Cryonic agents includedevices, such as cryostats, and cryogenic chemicals which are capable ofinducing low temperatures at the AV node.

The AV node blocker, capable of causing ventricular asystole, in apreferred embodiment is a cholinergic agent. As used herein, the term"cholinergic agent" refers to a cholinergic receptor modulator, which ispreferably an agonist. The cholinergic agent in a preferred embodimentis carbachol (carbamyl choline chloride). Other cholinergic agents whichmay be used include any naturally occurring cholinergic (acetylcholine)receptor agonists or synthetic derivatives. Exemplary cholinergic agentsinclude acetylcholine, methacholine, bethanechol, arecoline,norarecoline, pyridostigmine, neostigmine, and other agents thatincrease cyclic GMP levels by direct or indirect receptor stimulation.

In one embodiment, compositions and methods are provided which arecapable of slowing or preventing autonomous conduction of electricalimpulses from the sinoatrial node to the ventricle, with suppression ofescape beats in the AV node and the ventricle. Preferably, a state ofthe heart is induced wherein the heart beats less than about 25 beatsper minute, for example, less than about 12 beats per minute.

As used herein, the term "β-adrenergic blocking agent," also referred toas a "β-blocker", is defined as an agent which is capable of blockingβ-adrenergic receptor sites. In a preferred embodiment, the β-blocker ispropranolol. Other β-blockers which can be used include atenolol,acebutolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol,pindolol, sotalol and timolol. Other exemplary β-blockers includeceliprolol, betaxolol, bevantolol, bisoprolol, esmolol, alprenolol,carterolol, nadolol or teratolol, and mixtures thereof. The β-blockermay be any naturally occurring or synthetic analogue capable of blockingβ-adrenergic receptor sites.

In one embodiment, reversible ventricular asystole in a beating heart ina human patient is induced by administering to a patient a compositioncapable of suppressing autonomous ventricular electrical conduction andescape rhythms. In one embodiment, the composition capable of inducingventricular asystole may comprise a first compound capable of inducingventricular asystole, such as an AV node blocker, and a β-blockerpresent in an amount sufficient to substantially reduce the amount ofthe compound required to induce ventricular asystole. In one embodiment,the combination of the compound, such as an AV node blocker togetherwith the β-blocker provides a synergistic effect such that the amount ofAV node blocker required to induce reversible ventricular asystole maybe reduced in comparison to the amount of AV node blocker requiredalone. Methods also are provided wherein the β-blocker is administeredeither prior to or contemporaneously with the compound capable ofinducing ventricular asystole, in an amount effective to substantiallyreduce the amount of the compound required to be administered to induceventricular asystole.

In a particular embodiment, ventricular asystole is induced in a beatingheart in a human patient by administering a cholinergic receptor agonistand a β-blocker to the heart of the patient in an effective amount toinduce ventricular asystole, wherein the amount administered of thecholinergic receptor agonist alone or the β-blocker alone is notsufficient to induce ventricular asystole. In one embodiment, theco-administration of the β-blocker with the cholinergic agent provides asynergistic effect, such that the amount of cholinergic agent which isadministered to induce reversible ventricular asystole can be reduced.

Reversible ventricular asystole in the heart of a human patient thus maybe induced by administration of an AV node blocker, or mixture of AVnode blockers, to the heart of the patient. Reversible ventricularasystole optionally is induced by administration of the combination ofan AV node blocker, such as a cholinergic agent, and one or moreβ-blockers to the heart of the patient. The β-blocker is preferablyadministered either prior to or contemporaneously with the AV nodeblocker.

In an embodiment wherein a surgical procedure is to be conducted, afterinducing reversible ventricular asystole, the method further includeselectrically pacing the heart with an electrical pacing system, therebyto maintain the patient's blood circulation; selectively intermittentlystopping the electrical pacing to allow ventricular asystole; andconducting the surgical procedure during the intervals of time that theelectrical pacing is intermittently stopped.

The method may be used, for example, in a cardiac surgical procedure.Electrical pacing may be controlled by a surgeon conducting the surgicalprocedure by selectively manipulating a control that is functionallycoupled to the electrical pacing system. Once reversible ventricularasystole is achieved, pacing of the heart may be implemented using aexternal pacemaker connected to the heart, and the pacemaker may beperiodically deactuated, for example by way of a foot switch, to allowreversible ventricular asystole, thereby facilitating the performance ofcoronary artery bypass, with or without cardiopulmonary bypass, or otherprocedures elsewhere in the body of the patient.

For example, to conduct a coronary artery bypass, the patient's heart isprovided with ventricular pacing electrodes connected to an electricalpacing device, which is controlled by the surgeon. A composition, forexample, comprising an AV node blocker and a β-blocker, then isadministered to the patient to induce reversible ventricular asystole.The surgeon then employs the pacing device to pace the heart and sustainthe patient's circulation. The surgeon intermittently stops theelectrical pacing for a few seconds to place a single suture, andre-starts it after each successive suture, thus permitting a precisecoronary anastomosis to be performed. In this method, the ventricles(and/or atria) are electrically paced and maintain a normal cardiacoutput except for the brief periods of time that are required toaccurately place a single suture in the coronary artery, preferablyabout 2 to 15 seconds, and more preferably about 2 to 5 seconds. Usingthe methods and compositions described herein, the rate and timing ofventricular contraction can be directly controlled.

In the method, the composition inducing ventricular asystole, such as anAV node blocker in combination with a β-blocker or AV node blockeradministered after a β-blocker, may be infused through a catheter placedinto the right coronary artery.

In one embodiment, the composition is delivered locally to the AV nodeof the heart upon which it acts via the AV node artery of the heart.Preferably the composition is delivered to the right coronary arterywhich feeds blood to the AV node artery. In a majority of patients, theright coronary artery is the main vessel supplying blood to the rightside of the heart and to the AV node. However, where the right coronaryartery is substantially totally occluded, and in a small subset of about20% of patients, the first septal branch of the left anterior descendingartery which originates from the left coronary artery may be the vesselwhich delivers blood to the AV node and can be selected as the deliveryconduit for delivering the composition to the AV node. Additionally,other possible routes of administration to the AV node may includeKugel's artery and the right superior descending artery. Preferably, thecomposition is delivered to the right coronary artery or left coronaryartery at a location near the bifurcation to the AV node artery andproximal to the right coronary artery's bifurcation into the posteriordescending artery by any one of a number of drug delivery means, such asa drug delivery catheter suitably positioned within the right coronaryartery. Other methods of administration may be used including hypodermicneedle injection into, for example, any of the vessels noted above whichmay supply blood to the AV node, such as the right coronary artery orthe first septal branch. Other methods of administration include needleinjection into the aorta, needle injection directly into the AV nodeartery or the AV node itself, a transepicardial absorption pad, i.e., amyocardial patch which slowly releases the composition directly into theheart's myocardium, and for example, an intraoperative cannula or othersimilar guide introducer or sheath which can be surgically placed by asurgeon into the aorta or the ostium of a coronary vessel without theneed for X-ray fluoroscopy.

As the composition achieves the desired effect of ventricular asystole,the ventricle is electrically paced to maintain a stable rhythm andblood pressure. To interrupt the electrical pacing of the heart, thesurgeon uses a convenient control means, such as a foot pedal or handheld actuator, as shown in FIG. 1, and is thereby able to stop the heartas sutures are placed in the coronary arterial wall. Because the heartis motionless during the critical period as the surgeon places sutures,precision and safety are enhanced. The time required to place a singlesuture into the coronary artery preferably does not exceed 15 seconds,and is preferably about 2 to 5 seconds, most preferably about 2 to 4seconds. Thus, the compositions can permit the elimination of thetranslational motion of the beating heart.

Compositions capable of inducing ventricular asystole in a patient areprovided which in one embodiment include a cholinergic receptor agonistand a β-blocker, wherein the amount of the cholinergic receptor agonistalone or the β-blocker alone in the composition is not sufficient toinduce ventricular asystole in the patient. Methods are provided whereinthe cholinergic receptor agonist and the β-blocker may be administered,either sequentially or together, thereby to induce ventricular asystolein a patient, wherein the amount of the cholinergic receptor agonistadministered alone or the β-blocker administered alone is not sufficientto induce ventricular asystole in the patient.

In one embodiment, wherein a cholinergic agent and a β-blocker areadministered to the heart of a human patient to induce reversibleventricular asystole, when the β-blocker used is propranolol and thecholinergic receptor agonist used is carbachol, a continuous infusionrate of about 0.1 to 4.8 μg/kg/min of carbachol can be used, e.g., aninfusion rate of carbachol of 0.1 to 2.1 μg/kg/min, or about 0.1 to 1.5μg/kg/min, or in one preferred embodiment, about 1.5 to 2.1 μg/kg/min.When an initial bolus of propranolol is administered prior to or duringadministration of an initial bolus of carbachol, the ratio by weight ofpropranolol to carbachol in the bolus injections can range, for example,from about 1:2 to 35:1, or, in another embodiment, from about 1:1 to15:1, or, in another embodiment, from about 2:1 to 10:1, or, in anotherembodiment, is about 5:1.

In another embodiment, compositions capable of inducing ventricularasystole in a patient are provided, comprising a compound, such as anatrioventricular (AV) node blocker, and a β-blocker, wherein theβ-blocker is present in an amount sufficient to substantially reduce theamount of the compound required to induce ventricular asystole in thepatient. The AV node blocker is preferably a cholinergic agent. Due tothe synergistic effect of the presence of the β-blocker, the cholinergicagent may be present in the composition in a reduced amount which is,for example, about 1-90%, about 1-50%, or about 1-20%, or for example,about 2-14%, or in another embodiment about 80% or less, for exampleabout 50% or less, or about 10% or less by weight of the amount of thecholinergic agent alone required to induce ventricular asystole in thepatient. Advantageously, the co-administration of the β-blocker with theAV node blocker provides a synergistic effect, such that the amount ofAV node blocker which is administered to induce ventricular asystole maybe reduced.

Additionally, in the methods disclosed herein, ventricular asystole maybe induced in a patient by administration, together, or sequentially, ofa compound, such as an AV node blocker, together with a β-blocker,wherein the β-blocker is administered in an amount sufficient tosubstantially reduce the amount of the compound required to induceventricular asystole in the patient. In a preferred embodiment, thecompound is a cholinergic agent, such as carbachol. Due to thesynergistic effect of the administration of the β-blocker, thecholinergic agent may be administered in reduced amount which is, forexample, about 1-90%, about 1-50%, or about 1-20%, or in one embodiment,about 2-14%, or in another embodiment about 80% or less, about 50% orless, or about 10% or less by weight of the amount of the cholinergicagent alone required to induce ventricular asystole in the patient.

Additionally, due to the synergistic effect, the β-blocker may bepresent in combination with other compounds capable of inducingventricular asystole, in an amount effective to reduce the amount of thecompound required to induce ventricular asystole, for example to about5-90%, e.g., 30-50% or less by weight of the amount alone required toinduce ventricular asystole.

The administration of the β-blocker is preferably prior to, orcontemporaneously with, the administration of the cholinergic agent, andin one embodiment results in a synergistic effect between the β-blockerand the cholinergic agent. The amount of β-blocker present is preferablynot sufficient to induce ventricular asystole by itself, and issufficient only to cause a local β-blockade, but has a minimal effect onelectrical conduction of the heart, or is low enough to cause only afirst degree heart block.

In another embodiment, in order to induce reversible ventricularasystole in the heart of a patient, while maintaining the ability of theheart to be electrically paced, an AV node blocker is administered incombination with an effective amount of a second compound, such as aβ-blocker to reduce or suppress ectopic ventricular activity whilemaintaining the ability of the heart to be electrically paced. In oneembodiment, the β-blocker, alone or in combination with the AV nodeblocker, is capable of substantially suppressing ectopic ventricularbeats in the heart while maintaining the ability of the heart to beelectrically paced. For example, an AV node blocker, such as anantiarrythmic, such as flecainide, and a β-blocker, such as propranolol,may be administered. In one preferred embodiment, the β-blocker isadministered prior to the AV node blocker. In another embodiment, acomposition is provided that includes an AV node blocker and a β-blockerin an amount effective to induce reversible ventricular asystole andwherein the β-blocker is present in an amount effective to reduce orsuppress ectopic ventricular activity after administration.

The use of a cholinergic agent, such as carbachol, in combination with aβ-blocker, such as propranolol, preferably produces ventricular asystoleat significantly reduced dosages of the cholinergic agent, whilemaintaining a short half-life and rapid onset of effect. A preferredhalf-life is on the order of about one to ten minutes. A preferred onsetof effect is less than one minute after administration. It is possibleto induce onset of ventricular asystole within about thirty secondsafter administration of carbachol and propranolol to the heart.

The compositions preferably are capable of inducing reversible transientventricular asystole of a beating heart to facilitate the performance ofminimally invasive surgical procedures, while still permitting the heartto be electrically paced. The compositions, including for example acholinergic agent, preferably can reliably and in a dose-dependentfashion produce extended periods of reversible ventricular asystole, forexample, for up to about two hours upon either administration of asingle dose, or continuous infusion, depending upon the composition. Inpreferred embodiments, the ventricular asystole is chemicallyreversible. For example, in the case of carbachol, the ventricularasystole can be reversed by administering atropine, for example by anintravenous bolus injection, providing an important advantage of safetyduring the procedure.

In one preferred embodiment, to induce ventricular asystole, theβ-blocker is administered to the heart before the cholinergic agent. Forexample, the β-blocker in one embodiment is administered in a singlebolus injection into the right or left coronary artery, and then thecholinergic agent is administered by a single bolus injection followedby continuous infusion into the right or left coronary artery throughoutthe surgical procedure, to maintain the ventricular asystole. In anotherembodiment, where the β-blocker has a relatively short half life, suchas esmolal, the β-blocker may be administered by continuous infusion, ora plurality of bolus infusions. The ventricular asystole continues aslong as administration of the cholinergic agent is continued. In apreferred embodiment, due to the prior administration of the β-blocker,it is possible to administer a significantly reduced amount of thecholinergic agent and thereby reduce the occurrence of side-effects suchas systemic hypotension. Moreover, depolarization of the pacemaker cellsof the heart by the administered composition is preserved, therebymaking it possible to selectively electrically pace the heart to permitthe performance of a surgical procedure while the heart is undertransient ventricular asystole.

The time between administration of the β-blocker and the cholinergicagent is preferably long enough to permit the β-blocker to cause a localβ-blockade of the pacemaker cells of the heart. After bolusadministration, the time interval can be, for example about two minutes.In the case of intravenous or other forms of administration, severalminutes or even hours may be required to permit the β-blocker to affectthe pacemaker cells of the heart. The subsequent administration of thecholinergic agent may be controlled by the surgeon. Bolus infusion ofhigher doses can be used to give a dose dependent effect, whilecontinuous infusion of lower doses also may be given to maintainventricular asystole. In another embodiment, the β-blocker may beadministered by an initial intracoronary bolus followed by a continuousinfusion.

In one embodiment, the AV node blocker, such as a cholinergic agent,such as carbachol, is administered in an initial intracoronary bolus ofabout 0.1 to 150 μg/kg body weight of patient, or about 2 to 20 μg/kgbody weight of patient, for example, about 4 to 16 μg/kg, or about 6 to14 μg/kg, or in one embodiment, about 8 to 12 μg/kg body weight, in asuitable pharmaceutically acceptable carrier. The AV node blocker, suchas carbachol, is preferably administered over a time period of about 0.1to 3 minutes, preferably about 0.5 to 1 minute. In a preferredembodiment, the AV node blocker, such as a cholinergic agent, such ascarbachol, is administered in an intracoronary bolus of about 0.10 to 10μg/kg body weight of patient, for example about 0.10 to 5.0 μg/kg bodyweight in a pharmaceutically acceptable carrier over a time period ofabout 0.1 to 3 minutes, preferably about 0.5 to 1 minute.

The bolus infusion of the AV node blocker such as a cholinergic agent isin one embodiment followed by a continuous intracoronary infusion atabout 0.1-5 μg/kg body weight/min of the AV node blocker, which in apreferred embodiment is a cholinergic agent. The infusion rate in oneembodiment is about 0.1-4.8 μg/kg body weight of patient/min, forexample about 0.1-2.1 μg/kg/min, or about 0.1-1.5 μg/kg/min, or about0.1-1.0 μg/kg/min, or in another embodiment, about 0.1-0.5 μg/kg/min.Optionally, the cholinergic agent is combined with a β-blocker. In oneembodiment, a typical total adult dosage of an AV node blocker, such asa cholinergic agent, such as carbachol, is about 1 mg to 15 mg. Thisdosage can produce reversible ventricular asystole, for example, for atime period of about 5 to 120 minutes, for example, about 5 to 90minutes, preferably about 30 to 90 minutes, e.g., about 75 minutes. Thedosage may also be, for example, about 1 to 12 mg, or about 1 to 10 mg,or in one embodiment about 1 to 5 mg. The dosage may be adjusteddepending on the surgical procedure.

The β-blocker, such as propranolol, in one embodiment is administeredthrough the right or left coronary artery in a dosage of about 0.01 to0.07 mg/kg body weight of patient, for example, 0.01 to 0.05 mg/kg, orabout 0.01 to 0.04 mg/kg. The total amount of propranolol administeredis in one embodiment about 1 mg to 6 mg, e.g., about 1 mg to 5 mg, or,for example, about 2 to 4 mg, or about 3 mg.

For example, one embodiment to induce transient reversible ventricularasystole in a patient is as follows. An intracoronary injection of 0.5to 4 mg, e.g., about 1.0 mg, of propranolol is administered byintracoronary infusion through a drug delivery catheter positioned inthe right coronary artery just proximate to the AV node artery, over atime period of about 0.5-3 minutes, e.g., about 1 minute, preferablyfollowed by a saline flush, such as a 2 mL saline flush. This isfollowed by an intracoronary bolus injection of about 0.01 to 0.5 mg,e.g., about 0.025 to 0.3 mg, e.g., about 0.1 mg carbachol administeredover about 0.5 to 3 minutes, e.g., about 1 minute, and then by anintracoronary infusion of carbachol at a rate of about 0.01 to 0.3mg/min, e.g., about 0.025 to 0.3 mg/min, for example, about 0.01 to 0.1mg/min, or, e.g., about 0.05 to 0.1 mg/min, e.g. about 0.0825 mg/min,for a time period of about 5 to 90 minutes, preferably about 30 to 90minutes, e.g., about 75 minutes. A dosage amount of phenylephrine in therange of about 0.1 to 1.0 mg if needed may be administered to counteractany hypotension effects associated with carbachol administration.Additionally, nitroglycerine may be required in some patients tocounteract the coronary vasodilator effects of systemic phenylephrineadministration.

Additionally, in one embodiment, where the patient is under priortherapeutic treatment with a β-blocker, lower amounts of β-blocker, oralternatively no β-blocker may be required prior to the surgicalprocedure. Moreover, in certain situations overdrive suppression (i.e.,pacing at about 90 to 110 beats/min for about 10 seconds) may be used inaddition to the initial intracoronary bolus of carbachol and propranololto initiate ventricular asystole prior to carbachol continuous infusion.

Compositions may be administered by intravenous, intracoronary andintraventricular administration in a suitable carrier. Compositions maybe administered locally to the heart, for example, by direct infusion tothe right coronary artery as a single bolus injection, continuousinfusion, or combination thereof. T his can be achieved, for example byadministration to the proximal or ostial portion of the right coronaryartery, using a guiding catheter or drug delivery catheter, or byadministration just proximal to the AV node artery by means of a drugdelivery catheter positioned in the right coronary artery.Intraventricular (left side) injection also may be used. Continuousinfusion can be continued as long as necessary to complete theprocedure. In one embodiment, the infusion rate can range from about0.01 to 0.5 mg-min⁻¹, e.g., about 0.01 to 0.3 mg-min⁻¹, or about 0.015to 0.15 mg-min⁻¹, for example about 0.016 to 0.12 mg-min⁻¹. Methods ofadministration include intravenous, intra-atrial, intra-aortic, andadministration via the aortic root, or coronary artery. Administrationmay be via any suitable route, for example via the left or rightventricle, for example proximal to the AV node artery, or via the aorta,pulmonary artery, pulmonary vein, middle cardiac vein, right atrium orthe coronary sinus. In another embodiment, administration may be bydirect administration into the AV node artery or AV node. In oneembodiment, administration may be via a hypodermic needle to the AVnode.

In addition to local delivery, systemic delivery routes ofadministration known in the art may be used, such as oral, transdermal,intranasal, suppository and inhalation. For example, in addition toinjection as described above, the β-blocker may be administered orallyin a suitable carrier for oral administration. The patient also may beon therapeutic treatment with a β-blocker prior to the surgicalprocedure and thus may require lower amounts, or even no additionalβ-blocker prior to the surgery.

The compositions capable of inducing ventricular asystole, such as an AVnode blocker and β-blocker, may be provided in pharmaceuticallyacceptable carriers including diluents. A variety of carriers may beused that are known in the art, preferably in sterile form. Suitablecarriers include sterile water, aqueous normal saline solutions, andaqueous solutions such as lactated Ringer's solution, or a solution of asugar such as dextrose, for example 5% dextrose in water or saline.Other possible carriers, which may be provided, for example, in anaqueous solution, include sodium citrate, citric acid, amino acids,lactate, mannitol, maltose, glycerol, sucrose, ammonium chloride, NaCl,KCl, CaCl₂, sodium lactate, and sodium bicarbonate. In one embodiment,the carrier may be D5W, a solution of 5% dextrose in water. Othercarriers include buffered aqueous solutions, such as an acqueoussolution comprising 5 mM HEPES(N-[2-hydroxyethyl)piperazine-N'-[2-ethanesulfonic acid]). Antioxidantsor preservatives such as ascorbic acid also may be provided in thecompositions. Carriers known in the art, for example, for injection,oral delivery, delivery via a suppository, transdermal delivery andinhalation also may be used.

In one embodiment, compositions are provided which include an AV nodeblocker, such as a cholinergic agent and β-blocker either together orseparately in a pharmaceutically acceptable carrier. In anotherembodiment, containers containing unit dosage forms of the AV nodeblocker, such as a cholinergic agent and the β-blocker, either inseparate containers or in a single container are provided. In oneembodiment, unit dosage forms of carbachol and propranolol are providedeither in separate containers or in a single container foradministration to a patient, optionally in combination with apharmaceutically acceptable carrier. For example, carbachol can bepresent in a pharmaceutically acceptable carrier in a dosage form foradministration to a patient in an amount of about 5 to 150 μg/kg bodyweight of the patient, or in a total amount of from about 1 to 20 mg, orin a total amount of about 5 to 10 mg. The propranolol can be present ina pharmaceutically acceptable carrier in a dosage form foradministration to a patient in an amount of about 0.01 to 0.07 mg/kgbody weight of the patient, or in a total amount of about 1 to 10 mg, orin a total amount of about 1 to 5 mg. Carbachol is availablecommercially from Sigma Chemical Company, St. Louis, Mo.

Thus, in one aspect of the invention, there is provided a compositioncomprising an AV node blocker or a β-blocker, or a combination thereof,in a pharmaceutically acceptable carrier. The composition, may beprovided for example as an aqueous solution, or in the form of asuspension or emulsion. Optionally, the composition may include amixture of AV node blockers and/or a mixture of β-blockers. Thecomposition may be provided in a form suitable for parenteraladministration. In the embodiment wherein the composition compriseswater, the water is preferably processed, for example by compressiondistillation, to ensure that it is sufficiently purified to be suitablefor parenteral administration. Methods for making compositions of aquality suitable for parenteral administration are disclosed forexample, in Gennaro, "Remington: The Science and Practice of Pharmacy,"Mack Publishing Co., Easton, Pa., 1995, Vol. 2, Chapter 87, thedisclosure of which is incorporated herein. In one embodiment, thecomposition is provided in a form suitable for administration to thecardiovascular system during a surgical procedure. In one embodiment,the AV node blocker is a cholinergic agent. In a preferred embodiment,the AV node blocker is carbachol. The pharmaceutically acceptablecomposition comprising the AV node blocker or β-blocker, or combinationthereof, may be provided, for example in an aqueous solution, in acontainer, such as a vial, at a concentration suitable for directadministration to a patient, or may be diluted, for example with saline.

In one embodiment, a pharmaceutically acceptable composition comprisingan AV node blocker, such as cholinergic agent, is provided, which may beused to permit local cardiac administration of the AV node blocker. Inone embodiment, there is provided a pharmaceutically acceptablecomposition comprising carbachol, wherein the composition is suitablefor parenteral administration. Preferably, the carrier is suitable forintracoronary administration. The carbachol may be provided in anaqueous carrier, such as water. In the composition, which optionally maybe diluted prior to local cardiac administration, the concentration ofcarbachol may range, for example, from about 0.01 mg/mL to 2.55 mg/mL,e.g., about 0.1 to 1.0 mg/mL. In one embodiment, the composition mayfurther comprise a β-blocker, such as propranolol, at a concentration,for example, of about 0.5 to 6 mg/mL, for example about, 0.5 to 3 mg/mL,or, e.g., about 1.0 to 2.0 mg/mL or about 1.0 mg/mL. If needed, thecomposition may be diluted to a concentration suitable for localadministration to the heart, e.g., via an intracoronary bolus orinfusion.

Pharmaceutically acceptable compositions also are provided including anAV node blocker, such as a cholinergic agent and/or a β-blocker that aresuitable for direct local cardiac administration. In one embodiment,there is provided a pharmaceutically acceptable composition comprisingcarbachol, wherein the composition is suitable for direct localadministration, for example, to a coronary vessel such as the rightcoronary artery. The carbachol is, for example, provided in an aqueouscarrier, such as water. In one embodiment, the carbachol is provided inphysiologic saline. In the composition, the concentration of carbacholmay range, for example, from about 0.001 to 2.55 mg/mL, for example,about 0.01 to 2.5 mg/mL, or about 0.05 to 1.0 mg/mL, e.g., about 0.01 to0.5 mg/mL, for example, about 0.05 mg/mL to 0.2 mg/mL, or e.g., about0.1 to 0.2 mg/mL, or about 0.075 mg/mL. The composition may optionallyfurther comprise a β-blocker, such as propranolol, at a concentration,for example, of about 0.05 to 6.0 mg/ml, for example, 0.05 to 3.0 mg/ml,or, e.g., about 1.0 to 2.0 mg/ml, or about 1.0 mg/mL. In thisembodiment, the composition is suitable without dilution for localadministration to the heart, e.g., via an intracoronary bolus orinfusion.

In another aspect of the invention, there is provided a surgical kitincluding a container comprising a dosage of a cholinergic agent, suchas carbachol. In one embodiment, a surgical kit is provided thatincludes a first container comprising a cholinergic agent and a secondcontainer comprising a β-blocker, wherein in one preferred embodiment,the cholinergic agent is carbachol and the β-blocker is propranolol. Thecontainers may include respectively a preferred dosage form of thecarbachol and of the propranolol. The first container may include acarbachol in a pharmaceutically acceptable carrier, and the secondcontainer may include propranolol in a pharmaceutically acceptablecarrier. Alternatively, the cholinergic agent and the β-blocker may beprovided in a single container, optionally in combination with apharmaceutically acceptable carrier. The kit may further includeepicardial or endocardial pacing electrodes or any other disposableitems associated with the pacemaker. The kit-also may include a drugdelivery catheter and associated disposable items.

Referring to the drawings where like numerals indicate like elements,drug delivery and pacing apparatus are shown in accordance with theprinciples of the present invention. The pacing system generallyincludes pacer, a switch box and an actuator, which preferably can bereadily controlled by the physician to remotely control the pacerthrough the switch box. The pacing system will be described withreference to the example illustrated in FIG. 1. However, it should beunderstood that other configurations may be used.

Referring to FIG. 1, a pacing system configured in accordance with thepresent invention is shown. The illustrative system generally includes apacer 18, a switch or control box 14, and an actuator, such as actuator22 or 24. Pacer 18 may be a conventional ventricular demand pacer ordual chamber (atrial-ventricular) pacer. Leads 16 couple the output ofpacer 18 to switch box 14 and leads 12 couple switch box 14 to thepatent's heart. The latter may be achieved for example, eitherendocardially or epicardially. Switch or control box 14 preferably isconfigured so that when actuated, it delivers the pacing signals oroutput of pacer 18 to leads 12. Conductor or lead 20 couples remoteactuator 22 to switch box 14. Although a conventional foot pedal typeactuator is shown, it should be apparent from the foregoing andfollowing discussion that other actuators such as handle held actuator24 (shown in phantom) may be used. Further, as an alternative toepicardially or endocardially placed pacing leads, the leads may betransvenously delivered for coupling to the heart. In a furtheralternative, electrodes, such as transarterial electrodes, can beincorporated into the drug delivery catheter.

This pacing system of the present invention preferably provides to thesurgeon remote control of the on/off pacing function only. All otherparameters which are user selectable (rate, output, etc.) preferably arenot remotely programmable but must be adjusted by using controls on thepacemaker.

Referring to FIGS. 1A and 1B, circuit diagrams of the pacing system ofFIG. 1 are shown. Switch box 14 includes an electrical or mechanicalswitch 23 to which actuator 22 couples. This coupling allows the switchto be energized or deenergized as would be apparent to one of ordinaryskill. Preferably, foot pedal 22 is configured to be in an "Off"(electrically open) position when in its normal state and to be in an"On" (electrically closed) position to open switch 23 in switch box 14and interrupt delivery of pacing signals to the heart when the pedal isdepressed. Accordingly, if the power source to the pedal is interrupted,the heart will be paced. Alternatively, the foot pedal may be configuredto be in am "On" position when in its normal state and to be in an "Off"position when the pedal is depressed.

Returning to FIGS. 1A and 1B, switch box 14 preferably is configured ina manner to allow the pacing signal to pass through the box, to leads 12and, thus, to the patient while actuator 22 is in the "Off" position. Asshown in FIG. 1A, the switch box's switch 23 opens when the actuator isactivated (e.g., the foot pedal is depressed). This opening prevents thepacing signal from going to the patient. On the other hand, as shown inFIG. 1B, the switch box's switch 23 closes to again allow the pacingsignal to pass through to the patient, when the actuator is released.Commercially available switch boxes and foot pedal actuators may beused. For example, a suitable switch box with foot pedal is theTreadlight 2, Catalogue No. T-91-S manufactured by Line Master SwitchCorporation. This switch provides an open circuit when actuated as shownin FIG. 1A.

Safety features may be incorporated into the switch box. The first is atimer or override circuit, either programmable or factory set, thatlimits the time the switch or control box can interrupt the pacer. Thiscircuit overrides the actuator, if the actuator should happen to be helddown (i.e. in the "On" position) too long, i.e., longer than the presetmaximum time. The override circuit may be set or configured to overridethe activator after an interval of time of about 0.1-60 seconds, morepreferably about 5-30 seconds, or more preferably about 10-15 seconds.

A second safety feature is an indicator (visual and/or audible) thatindicates the pacing signal is not being sent to the patient. A thirdsafety feature is an indicator (visual or audible) that the pacingsignal is going out from the control box to the patient, especially tosignify the end of an interruption period (resumption of pacing).Preferably, the indicator or indicators are audible signals.

The control box could have additional features that may be more usefulfor the user than for safety. The first feature would be an indicator,preferably audible, preparing the user for the resumption of pacing.This could be a beeping tone that increases in frequency as theinterruption period ends. Second, the control panel should be batterypowered either by a disposable or re-chargeable battery. Other featuresinclude a control box that is preferably within 7"×10"×5", lightweight,less than 3 pounds, and easy to use with current pacer and pacing leaddesigns.

FIG. 1C presents one embodiment of the control box as schematicallyshown in FIGS. 1, 1A and 1B. As shown in FIG. 1C, a suitable control box14' includes debounce circuit 100, pull-down resistor 102, timer selectswitch 104, first timer 106, second timer 108, diodes 110, transistor112, inductive solenoid coil 114, switches 116, beeper control 118,volume control 120, and speaker 122.

Control box 14' uses debounce circuit 100 to generate a steady signalwhen mechanical foot pedal 22 is depressed. Debounce circuit 100 has aninput terminal 100A and an output terminal 1003B. The input terminalconnects to pull-down resistor 102. This terminal also connects to thefoot pedal switch 22A of foot pedal 22. When the foot pedal switch isopen as shown in figure 1C (e.g., when the operator does not depress thefoot pedal), the input terminal is pulled to ground through pull-downresistor 102. On the other hand, when the foot pedal switch closes(e.g., when the operator depresses the foot pedal), the input terminalconnects to the power supply voltage source through the foot pedalswitch 22 in order to receive the power supply voltage. In response tothe power supply voltage provided by mechanical foot pedal 22, thedebounce circuit generates a signal on its output terminal that itsteadily maintains at one level (e.g., the ground level) until the footpedal switch opens.

As shown in FIG. 1C, the output terminal 100B of the debounce circuit100 connects to first timer 106. The voltage on this output terminal isusually in a first level (e.g., the power supply voltage) when the inputto the debounce circuit is pulled to ground (i.e., when the foot pedalhas not been depressed). However, this output terminal's voltagetransitions to a second level (e.g., the ground voltage) when the inputto the debounce circuit transitions to the power supply voltage (i.e.,when the foot pedal has been depressed). As further described below, thevoltage at the output terminal 100B in combination with the signalsupplied to the reset pin 106C of the first timer circuit controls theoperation of this timer circuit.

Control box 14' uses first and second timer circuits 106 and 108 inorder to measure the lapse of a selected period of time. The amount oftime selected on time select rotary switch 104 is the maximum amount oftime that the physician can interrupt the supply of the pacing signal tothe heart by depressing the foot pedal. Once the control box 14'determines, through the use of timers 106 and 108, that the maximumamount of time has expired, then the control box 14' overrides (i.e.,ignores) the signal generated by the depressed foot pedal and resumesthe supply of the pacing signal to the patient. The second timer countsthe last five seconds in the selected period of time, while the firsttimer counts the remainder of time.

Both the timers 106 and 108 have reset pins (i.e., reset terminals) 106Aand 108A that receive the signal supplied to input terminal 100A ofdebounce circuit 100. When the signal supplied to the reset pin of atimer is low (i.e., when the foot pedal has not been depressed), thetimer enters its reset mode and resets its measured time value to itsinitial value. Each timer exits its reset mode and enters a standby modewhen the signal supplied to its reset terminal is high (i.e., when thefoot pedal has been depressed).

Also, each timer enters its operational modes when it receives a triggersignal at its input after it has entered its standby mode. Once thetimers are in their operational modes, they start counting up or down totheir expiration values when they receive an appropriate signal (e.g., ahigh voltage) on their input terminals 106A, 108A. First timer 106receives its trigger signal from the output of the debounce circuit.Thus, the transition of the output of the debounce circuit from onestate to another (e.g., goes from a high level to a low level) triggersthe operation of the first timer 106. Once triggered, the first timer106 starts to count towards its expiration value. The physiciandetermines the expiration value of the first timer by operating thetimer select switch 104, which connects to the first timer.

While the first timer operates (i.e., while it counts) and before it hasreached its expiration value, the signal at this timer's output terminal106B is at a first voltage level (e.g., the power supply level). Thesignal from output terminal 106B flows through diode 110A and issupplied to the gate of transistor 112 to turn ON this transistor.Transistor 112 can be any type of transistor. In FIG. 1C, thistransistor is an NMOS device.

Once transistor 112 turns ON, it draws current from the power supplythrough the inductive solenoid coil 114. This coil serves as a relay(i.e., coil that when energized operates a mechanical switch). Thus,when current passes through the solenoid coil, it activates the relaywhich opens switches 116A-D of patient connect relay 124. When the relayis deactivated, switches A-D couple the signal from the pacer to thepatient through leads 12.

Referring to the embodiment illustrated in FIG. 1C, switch 116A couplesa ventricle inlet (V-IN(-)) to a ventricle outlet (V-OUT(-)). Switch116B couples a ventricle inlet (V-IN(+)) to a ventricle outlet(V-OUT(-)). Switch 116C couples an atrial inlet (A-IN(-)) to an atrialoutlet (A-OUT(-)), while switch 116D couples an atrial inlet (A-IN(+))to an atrial outlet (A-OUT(+)). The inlets are coupled to the pacer andthe outlets are coupled to the patient. Referring to FIG. 1D, aschematic representation of an endocardial lead arrangement between thecontrol box and the right atrium of a patient is shown, together withthe coupling between the control box and the pacer. An actuator may becoupled to the control box as described above. The inlets (A-IN(-),A-IN(+)) may be coupled to the pacer 18 adapter cables and the outlets(A-OUT(-), A-OUT(+)) may be coupled to the patient with leads as shownin the drawing and as would be apparent to one of ordinary skill.Specifically, one lead may be coupled to positive terminal 140, which isin the form of a ring, and the other lead may be coupled to a negativeterminal 142, which may have a generally hemispherical configuration. Asimilar arrangement can be used to couple the control box to the rightventricle. Although an endocardial lead configuration is shown in FIG.1D, epicardial leads as shown in FIG. 1E may be preferred. Specifically,epicardial leads, which may be sutured to the heart (e.g., right atrium)as shown in FIG. 1E and generally designated with reference character"S", generally are preferred in open chest procedures since they can bereadily sutured to the heart. Again, a similar arrangement can be usedto couple the control box to the right ventricle.

Although the patient connect relay 124 is shown as a dual chamber pacingsystem, it should be understood that single chamber pacing systems canbe used to pace the ventricle as would be apparent to one of ordinaryskill in the art (e.g., by only using switches 16A and B shown in FIG.1C).

The output of the first timer is also supplied to a beeper controlcircuit 118, which controls the output of a speaker 122. Hence, when thefirst timer's output is active (i.e., its at a first voltage level, suchas the power supply level), it turns ON the beeper control circuit,which in turn generates a first audible signal through speaker 122.

When the first timer expires (i.e., when it has reached its expirationvalue), the signal at its output terminal transitions from the firstvoltage level to a second voltage level (e.g., transitions from thepower supply level to ground level). The first timer then enters itsstandby mode, where it will stay until it is reset by the opening of thefoot pedal switch.

The second timer has an edge detector (e.g., a negative edge detector)that detects this transition. Once it detects this transition, thesecond timer transitions into its operation mode, and thereby starts tocount towards its expiration value. The second timer's expiration valueis set at five seconds.

While the second timer is in its operation mode and has not reached itsexpiration value, the signal at its output terminal is at a firstvoltage level (e.g., the power supply level). In turn, diode 110Bsupplies this signal to the gate of transistor 112, and thereby keepsthis transistor ON. While transistor 112 is ON, it continues to drawcurrent through the coil 114, which, in turn, keeps switches 116A-D,which control delivery of the pacer signal to the patient, open.

The output of the second timer is also supplied to a beeper controlunit. Hence, when this output is active (i.e., its at a first voltagelevel, such as the power supply level), it turns ON the beeper controlunit, which in turn generates a second audible signal through speaker122.

Finally, it should be noted that the output of the timers resets to thesecond voltage level (e.g., ground) whenever the foot pedal switch opensand the timers are reset. This resetting operation overrides thecounting operation of the timers. Thus, if the timers are in the processof counting, the opening of the foot pedal makes these timers stopcounting and reset. Any suitable timers may be used such as 555 timersmanufactured by National Semiconductor (Santa Clara, Calif.).

As an alternative to foot pedal 22, a conventional needle holder 24 canbe used to control the pacer switch box. In this case, the needle holderpreferably is of the standard Castro-Viejo variety. However, any othermanual switch actuator operable by the surgeon for opening and closingthe switch in switch box 14 on demand can be used in accordance with theinvention to electrically connect and disconnect pacer 18 with pacingleads 12. Thus, the actuator can be incorporated in or on one of thesurgeon's instruments, such as surgical site retractor, or any otherlocation easily and quickly accessed by the surgeon.

Any conventional pacer suitable for ventricular demand pacing and havingexternal leads that can be electrically coupled to a switch box 14 maybe used. An example of such a suitable pacer is the Medtronic model 5330or 5375, Demand Pulse Generator manufactured by Medtronic Inc.(Minneapolis, Minn.)

It should be understood that although a particular pacing configurationis shown, other configurations may be used. For example, the pacer andswitch box may be combined in a single unit. If the switch box isincorporated in a pacer (i.e., pacemaker), specifications of thepacemaker should be similar to currently manufactured externalpacemakers (e.g., Ventricular or atrial-ventricular sequential; Raterange: 30 to 180 ppm (pulses per minute), continuously adjustable or inincrements of 1 ppm; Output current range: 0.1 to 20 mA; Sensitivityrange: 1.0 mV(maximum) to asynchronous; Pulse width: 1.8 ms maximum).

Pacer 18 preferably is an extracorporeal pacer and differs fromimplantable pacemakers in the following ways. Pacer 18 typically will bein excess of 400 grams, can use replaceable (battery life ofapproximately 500 hours) or rechargeable batteries (9v), may be linepower designed to last several years, and need not be constructed with abiocompatible exterior shell or be hermetically sealed.

Further, the pacing system may be configured to synchronize activationand deactivation of the patient's ventilator (not shown) with pacing.For example, the control box may be configured for coupling to aventilator so that pacing and ventilator signals are simultaneouslydelivered to the patient leads 12 and the ventilator when the actuatoris in a first state (e.g., when the foot pedal is released). In thisexample, the pacing and ventilator signals are simultaneouslyinterrupted when the actuator is in a second state (e.g., when the footpedal is depressed). The synchronization of pacing with a ventilator mayminimize or eliminate unwanted heart motion associated with a patient'sbreathing with a ventilator.

With an understanding of the pacing system in hand, drug deliveryaccording to the principles of the invention will be described withreference to FIGS. 2-7. Generally, FIGS. 2 and 3 show delivery into thecoronary sinus (FIG. 4 shows an alternative balloon configuration); FIG.5 shows intra-aortic delivery; and FIGS. 6 and 7 show delivery throughthe right coronary artery. Discussion of a further delivery procedure inaccordance with the present invention, intraventricular injection, alsowill be provided.

Coronary Sinus Injection

Referring to FIGS. 2, 2A, 3, and 3A, a coronary sinus delivery catheter30 is shown for local drug administration into the coronary sinus (CS)according to the present invention. Coronary sinus delivery catheter 30preferably is a medium-diameter, e.g. about 6-8 French, single or duallumen, flexible catheter. The tip of catheter 30 may be curved slightlyto give a so-called hockey-stick appearance as shown in the drawings.This configuration facilitates, for example, introducing the catheterinto the coronary sinus from the atrium as shown in FIG. 2 where thedistal tip is shown prior to introduction into the coronary sinus. Alow-pressure balloon 32 of up to about 2 cm in diameter is located nearthe tip of the catheter. Two ports 34, 36 are present at the proximalportion of catheter 30 for balloon inflation and drug injection,respectively. Catheter 30 further includes inflation lumen 37 and drugdelivery lumen 39 (FIGS. 2A and 3A) which fluidly couple ports 34 and 36to balloon 32 and delivery or discharge opening 38.

Any of three catheter lengths may be used depending on whether thecatheter is introduced into the coronary sinus: (A) through the rightatrium or atrial appendage; (B) via the internal jugular or subclavianvein; or (C) via the femoral vein. A guidewire (not shown) is used tofacilitate transvenous placement, and a stiffer wire obturator (notshown) is provided for catheter insertion through the right atrialappendage.

Access to the right atrial appendage (approach A) requires an operativeapproach through the right chest or through the mediastinum. A plegetedpursestring suture (e.g. 4/0 polypropylene), which is conventional inthe art, is placed on the right atrium (RA) or atrial appendage, andcatheter 30 is secured in place with a Rumel-tourniquet. The transvenousapproaches (approaches B and C) require expertise in coronary sinuscannulation over a guidewire using fluoroscopic or echocardiographicguidance. The internal jugular or subclavian approach accesses thecoronary sinus via the superior vena cava (SVC) as shown in FIG. 2. Thefemoral vein approach accesses the coronary sinus via the inferior venacava (IVC).

After the catheter is placed in the coronary sinus using any of thethree approaches described above, the guidewire or obturator, which wasused to introduce the catheter into the coronary sinus, is removed.Injection port 36 is then connected to a three-way stopcock (not shown)for intermittent measurement of coronary sinus pressure andadministration of the composition(s) provided in accordance with thepresent invention. With inflation of the low-pressure balloon within thecoronary sinus (FIG. 3), a right ventricular pressure wave form isobserved. The inventive composition(s) is then administered as a bolusinjection through drug injection port 36 so as to be delivered at thedelivery port 38. Coronary sinus pressure during bolus injectiongenerally should not exceed about 30 mm Hg. Alternatively, thecomposition(s) may be administered as a bolus injection followed bycontinuous infusion or as a continuous infusion alone. Balloon inflationmay be rapid inflation/deflation balloon synchronized with theelectrocardiogram (ECG). Alternatively, the coronary sinus may beoccluded, partially or completely, for a period of about one or twohours. Balloon 32 may have a much thinner wall construction than balloon42 (discussed below) because it need not expand against arterialpressure. Previously placed pacing leads 12 permit ventricular pacingduring drug induced ventricular asystole. Removal of the catheter simplyrequires deflation of the balloon and closure of the atriotomy with thepursestring suture.

Referring to FIG. 4, another coronary sinus catheter configuration isshown. Catheter 30' is provided with laterally spaced balloons 32' whichare fluidly coupled to inflation lumen 39'. Drug delivery lumen 37'opens in a region between the balloons.

Intraventricular Injection

Another drug administration approach is intraventricular injection intothe left ventricle via a catheter (not shown). With this approach, thecatheter may be delivered in retrograde fashion through the arterialsystem, aorta and through the aortic valve into the left ventricle. Inthe alternative, a catheter or cannula may be inserted directly into theleft ventricle (preferably the apex) through a hole made by the surgeon.In a further alternative, a needle may be inserted directly into theleft ventricle.

Aortic Root Injection

Another drug administration approach is injection of drug into theaortic root with, for example, an intra-aortic delivery catheter 40 asshown in FIG. 5. This permits direct aortic administration ofcompositions in accordance with the invention during diastole whileproviding ventricular support analogous to an intra-aorticcounterpulsation device. Catheter 40 preferably is a dual lumen catheterprovided for rapid inflation and deflation of a durable, low-pressureballoon 42 arranged to inflate in synchronization with heart beat (e.g.,electronically synchronized with ECG "P" waves so that balloon 42inflates during diastole and deflates just before systole). Importantly,complete occlusion of the aorta by the catheter balloon 42 is notrequired for proper functioning of the device. Thus, risk of injury tothe aortic wall, for example, the aortic dissection, is minimized. As inthe embodiment discussed above, a balloon inflation port 44 and a druginjection port 46 are provided. Catheter 40 a drug delivery andinflation lumens similar to catheter 30 with the exception that the drugdelivery lumen in catheter 40 terminates with a discharge opening 48proximal to balloon 42 this configuration facilitates delivery of drugsin the vicinity of the coronary arteries. Catheter 40 may be insertedthrough a hole made by the surgeon in the wall of the aorta as shown inFIG. 5, for example, or endovascularly delivered via a percutaneouslycatheter insertion in the femoral artery. However, if a catheter isdesired to be delivered in a retrograde fashion through the arterialsystem (e.g. femoral artery and the aorta), the balloon and lumenconfiguration of catheter 30 or 30', for example, is preferred. Theballoon diameter may be larger to correspond with the larger size of theaorta and the balloon walls also may be constructed to withstand thegreater pressures in the aorta.

Returning to FIG. 5, which illustrates placement of catheter 40, apursestring suture (not shown) is placed on the aortic root and catheter40 is inserted into the ascending aorta and secured with a Rumeltourniquet. The intra-aortic balloon is inflated during diastole anddeflated during systole, using the patient's ECG signal forsynchronization. Drug delivery is given with a bolus infusion and/orcontinuous infusion. With drug induced ventricular asystole, the heartis electrically paced, as detailed herein below, permitting continuedintra-aortic counterpulsation. In the case of where the accompanyingprocedure is a coronary artery bypass procedure, catheter 40 is removedafter the distal anastomosis is completed. Then, a partially occludingclamp is placed on the aorta, and the aortitomy may be used for theproximal aortosaphenous anastomosis. Alternatively, the catheter 40 maybe removed and the aortic pursestring simply tied.

Direct Infusion Into Right Coronary Artery

Another drug administration approach is direct infusion into the rightcoronary artery (RCA). This approach advantageously delivers drug morelocal to the AV node than the approaches described above. Other methodsare generally less efficient because when mixed in the aorta, ventricle,or other parts of the cardiovascular system, significant drug dilutionoccurs by the time it reaches the AV branch of the RCA.

This approach can be achieved by either injection into the proximal orostial portion of the RCA, by use of a guide catheter or drug deliverycatheter, or by injection just proximal to the branch perfusing the AVnode (AV node artery) by means of a drug delivery catheter positioned inthe RCA as shown in FIG. 6. Alternatively, the drug delivery cathetercan be positioned directly in the AV node artery through the RCA todelivery the drug more locally to the AV node. The catheter may beintroduced into the coronary artery via the arterial system (femoral,radial, subclavian) with a larger diameter coronary guiding catheter. Incases of a left dominant system anatomy or occluded RCA, the cathetermay be used in a similar fashion to deliver the drug into the leftcoronary artery to, for example, the circumflex branch.

Referring to FIG. 6, an exemplary catheter design as shown in thedrawings. Catheter 50 is a small diameter (for example, about 3-4French) single lumen catheter with a drug delivery opening 58 located atthe distal end of the catheter to provide selective coronary artery drugdelivery. By avoiding the need for a separate channel for ballooninflation, catheter 50 maximizes the volume of catheter lumen dedicatedto drug delivery while minimizing catheter diameter.

In use, catheter 50 is introduced into the right coronary artery underflouroscopic guidance through a larger diameter (6-8 French) coronaryguiding catheter 56, which is positioned at the ostium, and over aguidewire which is placed distally in the RCA.

After appropriate positioning of the catheter tip, just proximal to orwithin the take-off of the artery to the atrioventricular node branch(B) the guiding catheter is pulled back from the ostium of the RCA toprovide blood flow to the RCA, the guidewire is removed, and a bolusdose is given. Alternatively, a continuous infusion of drugs can beadministered into the distal right coronary artery. Coronary catheter 50is small enough that blood flow is not significantly impeded to the RCA.

Referring to FIGS. 7 and 8, another embodiment for the coronary deliverycatheter is shown. Catheter 60 is the same as catheter 50 with theexception that catheter 60 has a bent distal end portion 62. Catheter 50or portion 62 can be positioned within the branch (B) to the AV node.The bent distal end configuration minimizes or eliminates thepossibility of the catheter entering the branch going down a posteriorleft ventricular branch.

Although particular drug administration routes have been described, itshould be understood that other routes may be used including, withoutlimitation, needle injection into the aorta, needle injection into theAV node, and trans-epicardial absorption (e.g., a trans-myocardial patchwhich slowly releases pharmaceutical agents into the myocardium).

Pacing

Prior to drug delivery, the heart is prepared for cardiac pacing asdiscussed above. In general, leads 12 may be temporarily affixed to theright ventricle of the heart such as by suturing or other manner aswould be apparent to one of skill in the art. Drugs are administered tothe heart through, for example, any one of catheters 30, 40, 50 or 60 toinduce ventricular asystole. Pacing of the heart is established andmaintained. The pacing can be transiently interrupted by temporarilydeactivating the pacemaker using, for example, foot pedal 22. When thefoot pedal is in its deactuated, raised position, the switch in thepacer switch box is closed, and current flows from the ventriculardemand pacer 18, through the switch box 14 and the pacing wires 12 tothe heart 10 without impediment. During this time, the heart preferablyis paced at a rate between 90 to 110 beats/minute. When complete heartblock is necessary, to enable a surgical procedure to be performed,pacing is disabled by depressing the foot pedal. In the illustrated andcurrently preferred embodiment, this opens the switch in pacer switchbox 14, stopping the current flow from pacer 18 to pacing leads 12.Since no current reaches the heart while the foot pedal is depressed,ventricular asystole occurs, thus allowing precise suturing or othermanipulative procedures to be performed. Once, e.g., a suture has beenapplied, the pacer may be reactuated by releasing the foot pedal,thereby to reestablish the electrical connection between the pacer 18and the pacing wires 12 and resuming pacing of the heart at theprescribed rate until another precise manipulation is required. Byproviding a surgeon-controlled device, such as with a foot pedal, remotefrom the pacer for controlling the pacer, the surgeon can have completeand immediate control over when pacing is interrupted, even though thesurgeon also has surgical instruments in his or her hands. This allowsthe surgeon to coordinate precisely the pacing of the heart to themanipulative step, thereby minimizing unnecessary and undesired cardiacarrest.

The pacer control box also may be configured to control interruption ofa patient's ventilator so that the pacing may be synchronized (e.g., theactuator activates pacing and ventilating equipment (not shown)simultaneously and deactivates pacing and the ventilating equipmentsimultaneously). Thus, the switch box can be electrically coupled to aventilator so that when the foot pedal described above is depressedpacing and ventilation are deactivated and when it is released, pacingand ventilation resume. This arrangement may eliminate some smallmotions of the heart associated with a patient's breathing during asurgical procedure.

The invention will now be described in more detail by reference to thefollowing non-limiting examples.

EXAMPLE 1

In Vivo Studies

The following comparative in vivo studies demonstrated the synergisticeffect of the use of the cholinergic agent carbachol in combination withthe β-blocker propranolol in stimulating ventricular asystole accordingto the present invention.

Eleven male crossbred swine weighing 20-25 kg were studied, eight ofwhich received carbachol alone and three of which received carbacholplus propranolol. The swine were sedated using 10 mg/kg IV ketamine.After 20 minutes, the animals were induced with 10 mg/kg IV thiopentalsodium and orotracheally intubated. The proper anesthetic plane wasmaintained with 1% Isoflurane. Periodic arterial blood gas samples wereobtained to guide ventilator management. The electrocardiograph wascontinuously monitored. Through a 7 Fr sheath in the left femoralartery, arterial blood samples were obtained and a micromanometer wasinserted to monitor central aortic blood pressure (Millar Instruments,Inc., Houston, Tex.). The heart was exposed through a median sternotomyand suspended in a pericardial cradle. Two temporary epicardial pacingwires were affixed to the right ventricle and connected to an externalpacemaker (Medtronic, Inc., Minneapolis, Minn.). The pacemaker wasmodified to permit deactuation by means of depressing a foot pedal.Through the femoral sheath, an AR-1 guide (Cordis Corp., Miami Lakes,Fla.) was placed into the right coronary artery. An 0.014-inch floppyguide wire was then advanced into the right coronary artery to the levelof the posterior descending coronary artery. The AR-1 guide was removedand a 2.5 Fr Tracker (Cordis Corp., Miami Lakes, Fla.) catheter wasinserted over the guide wire. Using dye injection, the catheter waspositioned just proximal to the take-off of the atrioventricular nodeartery. Carbachol (Sigma St. Louis, Mo.) solution was prepared the dayof the experiment and infused at a constant rate using a Harvard pump.

Animals received either carbachol alone or carbachol in combination withpropranolol (Inderal®, Wyeth Ayerst, Philadelphia, Pa.). All animalswere instrumented and allowed 10 minutes of hemodynamic stability.Before carbachol was administered, each subject received a 500 ml IVbolus of 0.9% sodium chloride. In the animals receiving carbachol alone,carbachol was continuously infused through the Tracker catheter atincreasing doses of 0.44, 0.62, 0.88, and 1.72 mg/min, until ventricularasystole was observed.

In the animals receiving carbachol plus propranolol, a 1 mg dose ofpropranolol (0.04-0.05 mg/kg) was administered through the Trackercatheter. Carbachol was then administered as a 0.5 mg intracoronarybolus (0.02 mg/kg) followed by a constant infusion. The infusion ratenecessary to achieve ventricular asystole was 0.03 mg/min (1.1 to 1.2μg/kg/min). After carbachol-mediated ventricular asystole was observed,the heart was paced at 100 beats/minute. At 60-second intervals, thepacemaker was turned off for five seconds to determine the underlyingcardiac rate and rhythm. The systolic blood pressure (SBP), diastolicblood pressure (DBP), and main arterial pressure (MAP) were recordedevery five minutes. The duration of ventricular asystole, defined inthis example as a heart rate less than twelve beats per minute, wasrecorded. Profound hypotension (SBP <60 mmHg) after the administrationof carbachol was treated with normal saline, intravenous bolusinjections of phenylephrine (0.02 mg/kg), or both. After 75 minutes, thecarbachol infusion was stopped and the time required to return to normalsinus rhythm was recorded. The results are set forth in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        CARBACHOL INTRACORONARY INFUSION                                                                infusion rate                                                                         carbachol                                                                             duration of                                                                            time to                               weight of carbachol dose ventricular NSR.sup.1                               animal (kg) (mg/min) (μg/kg/min) asystole (min) (min)                    ______________________________________                                          1 41 0.44 10.7 76                                                             2 41 0.44 10.7 75                                                             3 20 0.62 31.0 47                                                             4 20 1.72 86.0 87                                                             5 36 0.44 12.2 75 8                                                           6 45 0.44 9.7 53                                                              7 21 0.44 20.9 24                                                             8 21 0.88 41.9 76 3                                                         ______________________________________                                        CARBACHOL AND PROPRANOLOL INTRACORONARY                                         INFUSION                                                                                      infusion rate                                                                         carbachol                                                                             duration of                                                                            time to                               weight of carbachol dose ventricular NSR                                     animal (kg) (mg/min) (μg/kg/min) asystole (min)                          ______________________________________                                          1 25 0.03 1.2 75 5                                                            2 27 0.03 1.1 75 7                                                            3 26 0.03 1.2 63 15                                                         ______________________________________                                    

EXAMPLE 2

Treatment of Human Patients

Ten human patients were treated pursuant to an investigational new drugclinical trial following Institutional Review Board and FDA approval andinformed consent.

Repair of a leaky distal anastomosis was performed on 9 human patients(designated Patients 101-109) with stable coronary artery disease (CAD)following open-chest coronary artery bypass graft (CABG) surgery. Thestudy was conducted to assess the ability to induce pacemaker-dependentreversible ventricular asystole in patients on cardiopulmonary bypass(CPB) utilizing an aortic cross clamp undergoing an open-chest CABGprocedure. Established institutional techniques for preparation andconduct of CABG were used. At the end of the surgical procedure, andafter the aortic cross clamp was removed, the AV-node blocker carbacholand the beta-blocker propranolol were serially administered to thepatients to induce pacemaker-dependent ventricular asystole. In Patients101-109, the propranolol and carbachol were used at the end of the CABGsurgery only during repair of leaking distal vascular anastomoses, whilethe patients were still on cardiopulmonary bypass (CPB) subsequent tothe removal of the aortic cross clamp. In the tenth patient (designatedPatient 201), the carbachol and propranolol drugs and temporary pacingwere used for the CABG procedure itself, and the aortic cross clamp wasavoided.

The patients were selected based on the following key criteria. Patientswere selected ranging between 18 and 70 years in age with a normal sinusrhythm with P-wave-R-wave interval not exceeding 0.16 sec. Men or womenwere selected who had a stable coronary artery disease and wereundergoing elective CABG revascularization of distal target(s) in theleft anterior descending (LAD) artery system, right coronary artery(RCA) and/or the left circumflex (LCX) artery. Patients were selectedwith right dominant coronary circulation or an expectation that their AVnode was supplied by the RCA, and with the presence of at least two ofthe following angiographic criteria: (1) coronary arteries greater than2 mm in diameter, (2) noncalcified coronary arteries, or (3) an LAD thatwas not intramyocardial.

Patients with any of the following conditions were intended to beexcluded from the study: (1) significant left main coronary arterystenosis, (2) left dominant coronary circulation, (3) RCA with proximalchronic total occlusion or inability to pass drug infusion catheter pastproximal RCA stenosis, (4) presence of any significant hemodynamicinstability, including, but not limited to, unstable angina or activeischemia requiring maximal medical management, malignant ventriculararrhythmias currently requiring medical management or cardiogenic shockrequiring blood pressure support, (5) presence of any significantcondition that increases the risk of the CABG procedure or other studyprocedure, including but not limited to, a history of peripheralvascular disease, hypertensive heart disease, cardiomyopathy, New YorkHealth Association (NYHA) Class 3 or 4 congestive heart failure, chronicrenal insufficiency or failure, prior CABG, valvular heart disease,unusual body habitus (e.g., morbid obesity), presence of acute pulmonaryinfection/pneumonia, metastatic cancer, thyrotoxicosis, sepsis, historyof stroke or transient ischemic attack (TIA) or asymptomatic carotidbruit, (6) recent (within 2 weeks) acute myocardial infarction, (7)documented cardiac ejection fraction <30% within 30 days of plannedprocedure, (8) presence of any significant condition that would make thedetermination of the efficacy and/or safety endpoints of the study moredifficult, including, but not limited to, first or second degree heartblock, left or right bundle branch block or other IVCD, (9) presence ofany significant condition that increases the risk of exposure to any ofthe components of the drugs as follows: Propranolol--This includes, butis not limited to, significant asthma, obstructive lung disease,congestive heart failure, hypersensitivity to propranolol or otherbeta-adrenergic antagonists; Carbachol--This includes, but is notlimited to, asthma, obstructive lung disease, epilepsy, Parkinsonism,peptic ulcer disease, hepatic insufficiency, hypersensitivity tocarbachol or other cholinergic agonists (i.e., cholinomimetics oracetyl-cholinesterase inhibitors), (10) presence of any significantcondition that increases the risk of use of a temporary pacemaker. Thisincludes, but is not limited to, implanted permanent pacemaker, historyof ventricular tachycardia or fibrillation requiring currentantiarrhythmic therapy, other arrhythmia or condition that increases therisk of cardiac pacing, e.g., Wolfe-Parkinson-White syndrome, and (11)pregnant or nursing women.

For Patients 101-109, CABG surgery was performed using well establishedtraditional methods. Patients were placed on CPB, the aorta wascross-clamped and cardioplegic arrest was administered. After distal and(if applicable) proximal anastomoses were sutured, the cross-clamp wasremoved and (if necessary) the heart defibrillated with patients stillon CPB. When a leak requiring repair was detected at the distalanastomotic site(s), epicardial pacemaker leads were sewn into place onthe ventricles and, optionally, the right atrium, of the patients andthe pacing thresholds determined and recorded. A temporary pacemaker wasconnected to the epicardial leads. The pacing voltage was set at 10times the pacing threshold. The pacemaker was first placed inventricular-ventricular inhibited (VVI) mode with a rate of 60±15 bpmand pacing ensued for 2 minutes. Hemodynamic acceptability of theVVI-paced rhythm was assessed. The pacemaker was then set inventricular-atrial triggered (VAT) mode and pacing ensued for another 2minutes. Hemodynamic acceptability of the VAT-paced rhythm was assessed.

During surgery and prior to administration of the drug protocol,fluoroscopy was used to position an appropriate catheter, e.g., aTracker™ (Target Therapeutics, Freemont, Calif.) catheter with anappropriate guide wire, in the proximal right coronary artery. Thiscatheter was used for intracoronary administration of the study drugs.If at any time during the procedure, catheter displacement was noted,repeat angiography was used to reposition the catheter. Adequatesupplies of phenylephrine, other adrenergic agents and volume repletionfluids were available at the bedside during and following drugadministration in the event of unexpected adverse events, to controlblood pressure, and/or to protect against inadvertent overdose.

The propranolol solution used was an injectable solution of Inderal®(Wyeth-Ayerst, Philadelphia, Pa.). The initial propranolol dose was 1 mgof a 1 mg/mL solution. Carbachol was provided in a vial containing 6 mLof a 0.255% solution (mg/dL). Each vial contained 2.55 mg/ml ofcarbachol in 5 mM sodium citrate and was adjusted to pH=7.0 using citricacid. The carbachol infusion solution was prepared by adding 5 mL ofthis solution to 250 mL of sterile saline. After reconstitution, theresulting concentration of the carbachol solution was 0.005%, or 0.05mg/mL. The initial dose of carbachol was 0.025 mg or 0.5 mL and theinitial infusion rate was 0.025 mg/min or 0.5 mL/min of the 0.005%solution.

A loading dose of propranolol ranging between 1-6 mg first was given topatients over a period of 1-3 minutes. Carbachol was administered as anintracoronary low dose bolus and as an infusion. For Patients 101-108,the bolus dose of carbachol used to initiate reversible ventricularasystole was in the range of 0.05-0.225 mg and the sustained infusion ofcarbachol used to maintain ventricular asystole was in the range of0.05-0.15 mg/min. In one of the patients studied, overdrive pacing wasused in conjunction with the loading dose of carbachol to induceventricular asystole. Once complete heart block was achieved with noventricular escape beats, and a pacemaker-dependent rhythm established,for patients 101-108 the distal anastomosis(es) were repaired duringbrief (up to 5 seconds) interruptions of pacing.

For Patient 201, the drugs and temporary pacing were used for the CABGprocedure itself. A loading dose of 4 mg propranolol and 0.15 mg ofcarbachol were administered via intracoronary delivery to Patient 201 toinitiate reversible ventricular asystole. Subsequently, an infusion ofcarbachol at a rate of 0.1 mg/min was given via intracoronary deliveryto the patient to maintain ventricular asystole for a period of about 45minutes. During this arrest period, a left internal mammary artery andobtuse marginal graft procedure were performed by the surgeon usingintermittent pacing interruptions to successfully place the distal graftanastamosis sutures on a substantially still rather than moving heart,producing the benefit of an improved technical result and avoidance ofcross-clamping of the aorta.

A dose of phenylephrine ranging between about 0.24-0.80 mg wasadministered to Patients 101, 103, 105-109 and 201 to controlhypotension. When a satisfactory technical result had been achieved, thedrug infusion was stopped and atropine was administered to determine thereliability of pharmacologic reversal of complete heart block with theexception of Patient 201, who was allowed to return to normal sinusrhythm naturally, over less than 15 minutes. The dosage amount ofatropine used to reverse arrest in Patients 101-108 was about 1.0 mg. Atthe close of the pharmacologic protocol, after resumption of normal A-Vconduction, CPB was removed. Established procedures for closing of thechest were followed.

In one patient, Patient 109, no arrest was achieved, howeverretrospective review of the post-operative angiogram revealed that thepatient was a left dominant patient, i.e., having the AV node fed fromthe left coronary artery rather than the right coronary artery, wherethe catheter was placed. Transesophageal echocardiography (TEE) revealednormal left and right ventricular function, i.e., with no reportedglobal or regional wall motion abnormalities in each patient in whicharrest was achieved.

The results are shown in Table 2 below.

                  TABLE 2                                                         ______________________________________                                                     Propra-                                                              nol Carba-                                                                   Minutes total chol Carbachol  Hypotension-                                   Pa- of dose- bolus- Infusion  phenylephrine                                   tient Arrest mg total mg mg/min Arrest used                                 ______________________________________                                        101  7       3       0.15  0.10   Yes   Yes                                     102 13 1 0.05 0.05 Yes No                                                     103 10 2 0.075 0.05 Yes Yes                                                   104 4 3 0.225 0.1 Yes No                                                      105 8 2 0.075 0.075 Yes Yes                                                   106 12 3 0.1 0.075 Yes Yes                                                    107 5 4 0.125 0.15 Yes Yes                                                    108 2 3 0.2 0.1 Yes Yes                                                       109  6 0.5 0.125 No Yes                                                       201 45 4 0.15 0.1 Yes Yes                                                   ______________________________________                                    

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A pacing system comprising:an extracorporealpacer for delivering pacing signals to a human heart; a switch coupledto said pacer; and an actuator arranged remote from said pacer andcoupled to said switch, wherein said actuator comprises a foot pedal. 2.A pacing system comprising:an extracorporeal pacer for delivering pacingsignals to a human heart; a switch coupled to said pacer; and anactuator arranged remote from said pacer and coupled to said switch,wherein said actuator comprises a needle holder.
 3. A pacing systemcomprising:an extracorporeal pacer for delivering pacing signals to ahuman heart; a switch coupled to said pacer; and an actuator arrangedremote from said pacer and coupled to said switch, wherein the actuatoris arranged remote from the switch.